Precision pharmaceutical 3D printing device

ABSTRACT

Provided herein are devices and systems for depositing a material or manufacturing a product, such as a pharmaceutical dosage form, by additive manufacturing. Further provided are methods of using the devices and systems, as well as methods of manufacturing a product, such as a pharmaceutical dosage form, by additive manufacturing. In certain embodiments, the device includes a material supply system configured to melt an pressurized a material, a pressure sensor configured to detect a pressure of the material within the device, and a control switch comprising a sealing needle operable in an open position and closed position. The sealing needle extends through a feed channel containing the material and includes a taper end, wherein the tapered end of the sealing needle engages a tapered inner surface of a nozzle to inhibit flow of the material through the nozzle when the sealing needle is in the closed position.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of InternationalApplication No. PCT/CN2019/070634, filed on Jan. 7, 2019; which claimsthe priority benefit of International PCT Application No.PCT/CN2018/071965, filed on Jan. 9, 2018; the entire contents of each ofwhich are incorporated herein by reference for all purposes.

TECHNICAL FIELD

The present invention relates to systems and devices for additivemanufacturing, and methods of using such devices. The present inventionfurther includes methods of making a product, such as a pharmaceuticaldosage form, by additive manufacturing.

BACKGROUND

Additive manufacturing, also referred to as three-dimensional printing,allows for the manufacture of products by extruding a melted materialinto a shape according a computer model. A computer system operates thethree-dimensional printer, and controls material flow and movement of aprinting nozzle until the desired shape is formed. In a fused filamentfabrication process (also known as fused deposition modeling), materialin the form of a filament is fed through a heated head, which melts thematerial onto a surface. The surface or the heated head can move toextrude the melted material into a set shape, as instructed by thecomputer system. Other additive manufacturing methods utilizenon-filamentous materials that are melted and pressurized before beingextruded through a printing nozzle, but such methods often result inundesirable leakage from the printing nozzle, particular when the meltedmaterial is viscous.

Recent developments in additive manufacturing has allowed for the use ofa large number of different three-dimensional printing processes and theuse of a many different materials. For example, biologically inertmaterials can be used in additive manufacturing processes for theproduction of implantable medical devices or custom laboratoryconsumables. See, for example, Poh et al., Polylactides in AdditiveBiomanufacturing, Advanced Drug Delivery Reviews, vol. 107, pp. 228-246(2016). Progress has also been made in developing additive manufacturingtechnology for the manufacture of pharmaceutical products. See Goyaneset al., 3D Printing of Medicines: Engineering Novel Oral Devices withUnique Design and Drug Release Characteristics, Molecular Pharmaceutics,vol. 12, no. 11, pp. 4077-4084 (2015).

Current additive manufacturing technology is limited, however, by theprecision in which three-dimensional printers extrude material.Pharmaceuticals need to be carefully controlled to ensure manufacturedproducts are uniformly shaped and contain a precise and accurate dosageof drug. There continues to be a need to develop precise systems foradditive manufacturing processes, including for the use manufacturingpharmaceutical products.

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein are hereby incorporatedherein by reference in their entirety.

SUMMARY OF THE INVENTION

Described herein is a device for depositing a material by additivemanufacturing, comprising: a material supply system configured to meltand pressurize the material, comprising a feed channel connected to aprinting head comprising a nozzle, the nozzle comprising a tapered innersurface and an extrusion port configured to dispense the material; apressure sensor configured to detect pressure of the material within thenozzle or the feed channel proximal to the nozzle; and a control switchcomprising a sealing needle operable in an open position and a closedposition, the sealing needle extending through a portion of the feedchannel and comprising a tapered end; wherein the tapered end of thesealing needle engages the tapered inner surface of the nozzle toinhibit material flow through the nozzle when the sealing needle is inthe closed position.

In some embodiments, the material is non-filamentous. In someembodiments, the material has a viscosity of about 100 Pa·s or more whenextruded from the device. In some embodiments, the material has aviscosity of about 400 Pa·s or more when extruded from the device. Insome embodiments, the material melts at about 50° C. to about 400° C. Insome embodiments, the material is extruded from the nozzle at atemperature of about 50° C. to about 400° C. In some embodiments thematerial is extruded from the nozzle at a temperature of about 90° C. toabout 300° C.

In some embodiments, any portion of the sealing needle that contacts thematerial is free of protrusions.

In some embodiments, the pressure sensor is connected to a computersystem that operates the material supply system to pressurize thematerial to a desired pressure in response to the pressure reported bythe pressure sensor. In some embodiments, the pressure of the materialis within about 0.05 MPa of the desired pressure. In some embodiments,the material supply system comprises a piston and a barrel connected tothe feed channel, and wherein the piston is operated to control pressureof the material within the barrel. In some embodiments, the piston isoperated using a stepper motor. In some embodiments, the pressure sensoris positioned proximal to the nozzle.

In some embodiments, the tapered end of the sealing needle comprises apointed tip. In some embodiments, the tapered end of the sealing needleis frustoconical. In some embodiments, the tapered inner surface of thenozzle has a first taper angle and the tapered end of the sealing needlehas a second taper angle; and wherein the second taper angle is the sameor smaller than the first taper angle. In some embodiments, the secondtaper angle is about 60° or less. In some embodiments, the second taperangle is about 45° or less. In some embodiments, the ratio of the firsttaper angle to the second taper angle is about 1:1 to about 4:1.

In some embodiments, the extrusion port has a diameter of about 0.1 mmto about 1 mm. In some embodiments, the tapered end has a largestdiameter of about 0.2 mm to about 3.0 mm. In some embodiments, theextrusion port has a diameter and the tapered end has a largestdiameter, and the ratio of the largest diameter of the tapered end tothe diameter of the extrusion port is about 1:0.8 to about 1:0.1.

In some embodiments, the control switch comprises an actuator thatpositions the sealing needle in the open position or the closedposition. In some embodiments, the actuator is a pneumatic actuator. Insome embodiments, the actuator is a mechanical actuator. In someembodiments, the actuator is an electric motor actuator. In someembodiments, the electric motor actuator is a linear stepper motoractuator.

In some embodiments, the sealing needle passes through a gasket fixed inposition relative to the nozzle, wherein the gasket seals the feedchannel.

In some embodiments, the material supply system comprises one or moreheaters configured to melt the material. In some embodiments, thematerial supply system comprises one or more temperature sensorsconfigured to detect the temperature of the melted material. In someembodiments, the one or more temperature sensors are connected to acomputer system that operates the one or more heaters in response to atemperature reported by the one or more temperature sensors.

In some embodiments, the tapered end of the sealing needle or thetapered inner surface of the nozzle comprises a flexible pad or liner.

In some embodiments, the device further comprises a computer systemcomprising one or more processors and a computer readable memory,wherein the computer system is configured to operate the device. In someembodiments, the computer readable memory comprises instructions forprinting a product using the device. In some embodiments, the computerreadable memory comprises instructions for controlling the pressure ofthe material in response to a pressure detected by the pressure sensor.In some embodiments, the computer readable memory comprises instructionsfor controlling the temperature of the material in response to atemperature detected by the temperature sensor. In some embodiments, thecomputer readable memory comprises instructions for positioning thesealing needle based on the instructions for printing the product. Insome embodiments, the instructions for positioning the sealing needlecomprise instructions for selecting an opening distance of the sealingneedle based on a desired flow rate of the material from the extrusionport.

In some embodiments, there is provided an additive manufacturing systemcomprising a plurality of the above-described devices, wherein eachmaterial supply system is configured with a control switch. In someembodiments, the system comprises a first device from the plurality ofdevices loaded with a first material, and a second device from theplurality of devices loaded with a second material, wherein the firstmaterial and the second material are different. In some embodiment, thecontrol switch of each device from the plurality of devices isdifferent. In some embodiment, the control switch of each device fromthe plurality of devices is the same. In some embodiments, the systemcomprises a computer system comprising one or more processors and acomputer readable memory, wherein the computer system is configured tooperate the system. In some embodiments, the computer readable memorycomprises instructions for printing a product using the system. In someembodiments, the computer readable memory comprises instructions forcontrolling the pressure of the material in each material supply systemin response to a pressure detected by the pressure sensor in thecorresponding material supply system. In some embodiments, the computerreadable memory comprises instructions for controlling the temperatureof the material in each material supply system in response to atemperature detected by the temperature sensor in the correspondingmaterial supply system. In some embodiments, the computer readablememory comprises instructions for positioning the sealing needle basedon the instructions for printing the product. In some embodiments, theinstructions for positioning the sealing needle comprise instructionsfor selecting an opening distance of the sealing needle based on adesired flow rate of the material from the extrusion port. In someembodiments, at least two of the devices from the plurality of devicescomprise: a material supply system configured to melt and pressurize thematerial, comprising a feed channel connected to a printing headcomprising a nozzle, the nozzle comprising a tapered inner surface andan extrusion port configured to dispense the material; a pressure sensorconfigured to detect a pressure of the material within the nozzle or thefeed channel proximal to the nozzle; and a control switch comprising asealing needle operable in an open position and a closed position, thesealing needle extending through a portion of the feed channel andcomprising a tapered end; and wherein the tapered end of the sealingneedle engages the tapered inner surface of the nozzle to inhibitmaterial flow through the nozzle when the sealing needle is in theclosed position. In some embodiments, the tapered inner surface of thenozzle has a first taper angle and the tapered end of the sealing needlehas a second taper angle; and wherein the second taper angle is the sameor smaller than the first taper angle. In some embodiments, the pressuresensor is positioned proximal to the nozzle.

In another aspect, there is provided a method of manufacturing a productby additive manufacturing, comprising: melting and pressurizing thematerial; flowing the material through an extrusion port of a nozzlecomprising a tapered inner surface; monitoring pressure of the materialwithin the nozzle or proximal to the nozzle; engaging a tapered end of asealing needle with the tapered inner surface of the nozzle, therebysealing the extrusion port and stopping flow of the melted material; andwithdrawing the tapered end of the sealing needle, thereby resuming flowof the material through the extrusion port. In some embodiments, themethod comprises receiving instructions for manufacturing the product.

In another aspect, there is provided a method of manufacturing apharmaceutical dosage form by additive manufacturing, comprising:melting and pressurizing a pharmaceutically acceptable material;monitoring pressure of the material within the nozzle or proximal to thenozzle; flowing the material through an extrusion port of a nozzlecomprising a tapered inner surface; engaging a tapered end of a sealingneedle with the tapered inner surface of the nozzle, thereby sealing theextrusion port and stopping flow of the melted material; and withdrawingthe tapered end of the sealing needle, thereby resuming flow of thematerial through the extrusion port. In some embodiments, thepharmaceutically acceptable material comprises a drug. In someembodiments, the pharmaceutical dosage forma has a desired drug releaseprofile. In some embodiments, the method comprises receivinginstructions for manufacturing the pharmaceutical dosage form.

In some embodiments of the methods described above, the pressure of thematerial within the nozzle remains approximately constant. In someembodiments, the method comprises controlling the pressure of thematerial using a feedback system based on the monitored pressure.

In some embodiments of the methods described above, the material isnon-filamentous. In some embodiments, the material has a viscosity ofabout 100 Pa·s or more.

In some embodiments of the methods described above, the any portion ofthe sealing needle that contacts the material is free of protrusions.

In some embodiments of the methods described above, the temperature ofthe material within the nozzle remains approximately constant. In someembodiments, the method comprises monitoring the temperature of thematerial. In some embodiments, the method comprises controlling thetemperature of the material using a feedback system based on themonitored temperature.

In some embodiments of the methods described above, comprisingwithdrawing the tapered end of the sealing needle to a selected openingdistance.

In some embodiments of the methods described above, the tapered end ofthe sealing needle comprises a pointed tip. In some embodiments, thetapered end of the sealing needle is frustoconical. In some embodiments,the tapered inner surface of the nozzle has a first taper angle and thetapered end of the sealing needle has a second taper angle; and whereinthe second taper angle is the same or smaller than the first taperangle. In some embodiments, the second taper angle is about 60° or less.In some embodiments, the second taper angle is about 45° or less. Insome embodiments, the ratio of the first taper angle to the second taperangle is about 1:1 to about 4:1. In some embodiments, the extrusion porthas a diameter of about 0.1 mm to about 1 mm. In some embodiments, thetapered end has a largest diameter of about 0.2 to about 3.0 mm. In someembodiments, the extrusion port has a diameter and the tapered end has alargest diameter, and the ratio of the largest diameter of the taperedend to the diameter of the extrusion port is about 1:0.8 to about 1:0.1.

In another aspect, there is a method of manufacturing a product byadditive manufacturing, comprising melting and pressurizing a firstmaterial; flowing the first material through a first extrusion port of afirst nozzle comprising a tapered inner surface; engaging a tapered endof a first sealing needle with the tapered inner surface of the firstnozzle, thereby sealing the first extrusion port and stopping flow ofthe melted first material; melting and pressurizing a second material;and withdrawing a tapered end of a second sealing needle from a taperedinner surface of a second nozzle, thereby initiating flow of the secondmaterial through a second extrusion port. In some embodiments, themethod comprises receiving instructions for manufacturing the product.

In another aspect, there is a method of manufacturing a pharmaceuticaldosage form by additive manufacturing, comprising melting andpressurizing a first pharmaceutically acceptable material; flowing thefirst pharmaceutically acceptable material through a first extrusionport of a first nozzle comprising a tapered inner surface; engaging atapered end of a first sealing needle with the tapered inner surface ofthe first nozzle, thereby sealing the first extrusion port and stoppingflow of the melted first pharmaceutically acceptable material; meltingand pressurizing a second pharmaceutically acceptable material; andwithdrawing a tapered end of a second sealing needle from a taperedinner surface of a second nozzle, thereby initiating flow of the secondpharmaceutically acceptable material through a second extrusion port. Insome embodiments, the first pharmaceutically acceptable material or thesecond pharmaceutically acceptable material is an erodible material. Insome embodiments, the first pharmaceutically acceptable material or thesecond pharmaceutically acceptable material comprises a drug. In someembodiments, the pharmaceutical dosage form has a desired drug releaseprofile. In some embodiments, the method further comprises receivinginstructions for manufacturing the pharmaceutical dosage form.

In some embodiments of the methods described above, the method furthercomprises monitoring pressure of the first material within the firstnozzle or proximal to the first nozzle; or monitoring pressure of thesecond material with the second nozzle or proximal to the second nozzle.In some embodiments, the pressure of the first material within the firstnozzle, or the pressure of the second material within the second nozzle,remains approximately constant. In some embodiments, the methodcomprises controlling the pressure of the first material or the secondmaterial using a feedback system based on the monitored pressure.

In some embodiments of the methods described above, the first materialor the second material is non-filamentous.

In some embodiments of the methods described above, any portion of thefirst sealing needle that contacts the first material, or any portion ofthe second sealing needle that contacts the second material, is free ofprotrusions.

In some embodiments of the methods described above, the temperature ofthe first material within the first nozzle, or the temperature of thesecond material within the second nozzle, remains approximatelyconstant. In some embodiments, the method comprises monitoring thetemperature of the first material or the temperature of the secondmaterial. In some embodiments, the method comprises controlling thetemperature of the first material using a feedback system based on themonitored temperature of the first material, or controlling thetemperature of the second material using a feedback system based on themonitored temperature of the second material.

In some embodiments of the methods described above, comprisingwithdrawing the tapered end of the second sealing needle to a selectedopening distance.

In some embodiments of the methods described above, the tapered end ofthe first sealing needle, or the tapered end of the second sealingneedle, comprises a pointed tip. In some embodiments of the methodsdescribed above, the tapered end of the first sealing needle, or thetapered end of the second sealing needle, is frustoconical.

In some embodiments of the methods described above, the tapered innersurface of the first nozzle has a first taper angle and the tapered endof the first sealing needle has a second taper angle; and wherein thesecond taper angle is the same or smaller than the first taper angle; orthe tapered inner surface of the second nozzle has a third taper angleand the tapered end of the second sealing needle has a fourth taperangle; and wherein the fourth taper angle is the same or smaller thanthe third taper angle. In some embodiments, the fourth taper angle isabout 60° or less. In some embodiments of the methods described above,the second taper angle or the fourth taper angle is about 45° or less.In some embodiments of the methods described above, the ratio of thefirst taper angle to the second taper angle, or the ratio of the thirdtaper angle to the fourth taper angle, is about 1:1 to about 4:1. Insome embodiments of the methods described above, the first extrusionport or the second extrusion port has a diameter of about 0.1 mm toabout 1 mm. In some embodiments of the methods described above, thetapered end of the first sealing needle or the tapered end of the secondsealing needle has a largest diameter of about 0.2 to about 3.0 mm.

In some embodiments of the methods described above, the first materialor the second material has a viscosity of about 100 Pa·s or more.

In some embodiments of the methods described above, the product or thepharmaceutical dosage form is manufactured in a batch mode. In someembodiments of the methods described above, the product or thepharmaceutical dosage form is manufactured in a continuous mode.

Also provided herein is the product or the pharmaceutical dosage formmade according to any one of the methods described above.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates an exemplary embodiment of a device for depositing amaterial by additive manufacturing according to the present invention.

FIG. 2A illustrates a cross-sectional view of an exemplary device fordepositing a material by additive manufacturing according to the presentinvention. FIG. 2B illustrates a zoomed in view of the printing head ofthe device shown in FIG. 2A, with the sealing needle in the closedposition and engaging the inner surface of the nozzle. Although FIG. 2Ashows a pneumatic actuator, an electric motor actuator (e.g., a linearstepper motor actuator) can be used. The electric motor actuator canposition the sealing needle at an open position between the closedposition and the maximum open position, such as at a position with aselected opening distance.

FIG. 3A shows a tapered end of a sealing needle with a pointed tip. FIG.3B shows a tapered end of a sealing needle with a frustoconical tip.FIG. 3C shows the taper of the inner surface of the nozzle.

FIG. 4 illustrates an exploded view of components of the pneumaticactuator that connect to the sealing needle to control the sealingneedle.

FIG. 5A shows a longitudinal section view of an exemplary device, withFIG. 5B showing a cross-sectional view of the exemplary device at plane“A-A,” and FIG. 5C showing a side view of the exemplary device. AlthoughFIGS. 5A-5C show a pneumatic actuator, an electric motor actuator (e.g.,a linear stepper motor actuator) can be used. The electric motoractuator can position the sealing needle at an open position between theclosed position and the maximum open position, such as at a positionwith a selected opening distance.

FIG. 6 illustrates another exemplary embodiment of a device as describedherein.

FIG. 7 illustrates a portion of an exemplary device that includes threematerial supply systems, each with a distinct printing head.

DETAILED DESCRIPTION OF THE INVENTION

The present application relates to a device for depositing a material byadditive manufacturing. The device includes a material supply system,which melts and pressurizes the material, which optionally includes adrug. In certain embodiments, the material is a non-filamentousmaterial. The material supply system includes a feed channel connectedto nozzle. The material, which may be pressurized and or melted in thefeed channel or upstream of the feed channel, flows through the feedchannel and is dispensed through the nozzle. Further provided herein aresystems for manufacturing a product by additive manufacturing, whichinclude two or more devices, each of which include a material supplysystem and a control switch. Also described herein are methods of usingsuch a device, as well as methods of manufacturing a product by additivemanufacturing and methods of manufacturing a pharmaceutical dosage formsby additive manufacturing.

When manufacturing products, particularly pharmaceutical products, it isdesirable to carefully control the amount of material that is dispensedby the nozzle. A significant problem with previous devices for additivemanufacturing is unintended leakage of the material through the nozzle,which can cause more than the desired amount of material to bedispensed. The problem is further complicated when using two or morenozzles, which may dispense different materials, that need to bealternatively switch on or off. For example, manufacturing defects ormaterial waste can arise if a first nozzle is leaking a first materialwhen a second nozzle is dispensing a second material. Because thedevices and systems described herein can handle a range ofpharmaceutical materials with high accuracy and precision of materialdeposition, the devices and systems are well suited to the fabricationof pharmaceutical dosage forms with complex geometry and composition.The devices, systems, and methods described herein also facilitatespersonalized medicine, including personalized doses and/or personalizedrelease profiles. Personalized medicine refers to stratification ofpatient populations based on biomarkers to aid therapeutic decisions andpersonalized dosage form design. Personalized drug dosage forms allowfor tailoring the amount of drug delivered, including release profiles,based on a patient's mass and metabolism. Pharmaceutical dosage formsmanufactured using the devices described herein could ensure accuratedosing in growing children and permit personalized dosing of highlypotent drugs. Personalized dosage forms can also combine all ofpatients' medications into a single daily dose, thus improve patients'adherence to medication and treatment compliance. Modifying digitaldesigns is easier than modifying physical equipment. Also, automated,small-scale three-dimensional printing may have negligible operatingcost. Hence, additive manufacturing using the devices described hereincan make multiple small, individualized batches economically feasibleand enable personalized dosage forms designed to improve adherence.

In certain embodiments, a customized pharmaceutical drug dosage formdesign with a desired release profile is received by a computer system,which is configured to operate the device or system described herein.The computer system can transmit instructions for manufacturing thepharmaceutical dosage form with the desired release profile to thesystem or device, which then manufactures the customized product. Insome embodiments, the computer readable memory comprises instructionsfor controlling the control switch. In some embodiments, the controlswitch comprises an electric motor actuator that positions the sealingneedle, and the computer readable memory comprises instructions forcontrolling the electric motor actuator to position the sealing needlein an open position (including open positions with various distancesbetween the end of the sealing needle and the extrusion port of thenozzle, up to a maximum open position) and a closed position.

The present invention provides for a more precise system for depositingmaterial or manufacturing a product (such as a pharmaceutical dosageform) by additive manufacturing by carefully controlling the pressure inthe nozzle or the feed channel proximal to the nozzle, and utilizing acontrol switch with a sealing needle that inhibits material flowingthrough the nozzle when the sealing needle is in the closed position.For example, a pneumatic actuator within the control switch may adjustthe sealing needle between an open position (such as a maximum openposition or a position with any distance between end of the sealingneedle and the extrusion port of the nozzle that allows for material toflow from the extrusion port of the nozzle) and a closed position. Whenthe control switch utilizes an actuator (such as a linear stepper motoractuator) that allows for various open positions (compared to a maximumopen/closed dual position switch), the amount and/or speed of materialextrusion can be modulated by adjusting the distance between theposition of the tapered end (e.g., tip of the tapered end) when thesealing needle is in an open position and the position of the taperedend when the sealing needle is in its closed position that completelyseals the extrusion port of the nozzle. This distance can be referred toas the “opening distance.” By controlling the amount and/or speed ofmaterial extrusion, the system can better synchronize the printingspeed. For example, for fine parts of a tablet, printing speed can beslowed down and material extrusion amount can be reduced; while fortablet portions that do not require too much precision, printing speedand material extrusion amount can both be increased, which may beachieved via increasing the opening distance of the sealing needlevalve, switching to a nozzle with larger diameter, or perfusion. Thenozzle includes a tapered inner surface, and the sealing needle includesa tapered end that engages the tapered inner surface of the nozzle tolimit material leakage. The sealing needle is preferably sharp, thin,and lacking protrusions that may push material out of the nozzle uponbeing positioned in a closed position. Pressure of the material ispreferably held approximately constant in the device, which can becontrolled by monitoring the pressure and using a feedback system toapply pressure to the material. This allows material to be immediatelyextruded at a constant rate once the sealing needle is positioned in anopened position without needing to ramp up pressure. This further allowsfor precise dispensing of the material, which allows for accurate andprecise manufacture of drug dose units, such as pharmaceutical tablets.

In some embodiments, there is provided a device for depositing amaterial or manufacturing a product (such as a pharmaceutical dosageform) by additive manufacturing, comprising a material supply systemconfigured to melt and pressurize the material, comprising a feedchannel connected to a printing head comprising a nozzle, the nozzlecomprising a tapered inner surface and an extrusion port configured todispense the material; a pressure sensor configured to detect pressureof the material within the printing head or the feed channel proximal tothe printing head; and a control switch comprising a sealing needleoperable in an open position and a closed position, the sealing needleextending through a portion of the feed channel and comprising a taperedend; wherein the tapered end of the sealing needle engages the taperedinner surface of the nozzle to inhibit material flow through the nozzlewhen the sealing needle is in the closed position. The open position canhave a selected opening distance from the extrusion port.

FIG. 1 illustrates an exemplary embodiment of a device for depositing amaterial or manufacturing a product by additive manufacturing accordingto the present invention. The device includes a material supply system102, which operates to melt and pressurize the material. Melted andpressurized material flows through a feed channel, which is connected toa nozzle 104. A pressure sensor 106 is positioned proximal to the nozzleand the terminus of the feed channel, and can detect the pressure of thematerial within the feed channel. Optionally, the pressure sensor 106can be configured to detect pressure of the material directly within thenozzle 104. A control switch 108 includes a linear actuator and asealing needle, and can operate the sealing needle in an open positionand a closed position. The linear actuator can be, for example, amechanical actuator (which may include, for example, a screw) ahydraulic actuator, a pneumatic actuator (which may include a pneumaticvalve), or a solenoid actuator (which may include a solenoid valve). Insome embodiments, the actuator comprises a pin cylinder, such as apneumatic pin cylinder. In some embodiments, the actuator comprises aspring-assisted pneumatic cylinder. In some embodiments, thespring-assisted pneumatic cylinder comprises a spring that assists inextending the sealing needle (i.e., positioning the sealing needle inthe closed position from the open position (e.g., maximum openposition)). In some embodiments, the spring-assisted pneumatic cylindercomprises a spring that assists in withdrawing the sealing needle (i.e.,positioning the sealing needle in the open position (e.g., maximum openposition) from the closed position). When the sealing needle is in anopen position, pressurized melted material can flow through the feedchannel and through an extrusion port of the nozzle 104. The amountand/or speed of the flow of the material through the extrusion port canbe modulated via adjusting the opening distance of the sealing needlevalve. When a signal is given to the control switch 108, for example,from the computer readable memory instructions, the control switch 108lowers the sealing needle in a closed position, and the tip of thesealing needle engages the inner surface of the nozzle 104.

In some embodiments, the material is a non-filamentous material, such asa powder, granules, a gel, or a paste. The non-filamentous material ismelted and pressurized so that it can be extruded through an extrusionport of a nozzle. As described further herein, pressure of particularlyviscous materials is carefully controlled to ensure precise and accuratedepositing of the material. The material can be melted within thematerial supply system using one or more heaters disposed within thematerial supply system, such as within or surrounding a barrelcontaining the material, a feed channel, and/or a printing head. In someembodiments, the melting temperature of the material is about 50° C. orhigher, such as about 60° C. or higher, about 70° C. or higher, about80° C. or higher, about 100° C. or higher, about 120° C. or higher,about 150° C. or higher, about 200° C. or higher, or about 250° C. orhigher. In some embodiments, the melting temperature of the material isabout 400° C. or lower, such as about 350° C. or lower, about 300° C. orlower, about 260° C. or lower, about 200° C. or lower, about 150° C. orlower, about 100° C. or lower, or about 80° C. or lower. Materialextruded from the nozzle can be extruded at a temperature at or abovethe melting temperature of the material. In some embodiments, thematerial is extruded at a temperature of about 50° C. or higher, such asabout 60° C. or higher, about 70° C. or higher, about 80° C. or higher,about 100° C. or higher, about 120° C. or higher, about 150° C. orhigher, about 200° C. or higher, or about 250° C. or higher. In someembodiments, the material is extruded at a temperature of about 400° C.or lower, such as about 350° C. or lower, about 300° C. or lower, about260° C. or lower, about 200° C. or lower, about 150° C. or lower, about100° C. or lower, or about 80° C. or lower.

The device described herein is useful for accurately and preciselyextruding viscous materials. In some embodiments, the material has aviscosity of about 100 Pa·s or more, such as about 200 Pa·s or more,about 300 Pa·s or more, about 400 Pa·s or more, about 500 Pa·s or more,about 750 Pa·s or more, or about 1000 Pa·s or more, when extruded fromthe device. In some embodiments, the material has a viscosity of about2000 Pa·s or less, such as about 1000 Pa·s or less, about 750 Pa·s orless, about 500 Pa·s or less, about 400 Pa·s or less, about 300 Pa·s orless, or about 200 Pa·s or less.

In some embodiments, the material is a pharmaceutically acceptablematerial. In some embodiments, the material is inert or biologicallyinert. In some embodiments, the material is an erodible material or abioerodible material. In some embodiments, the material is anon-erodible material or a non-bioerodible material. In someembodiments, the material is a pharmaceutically acceptable material. Insome embodiments, the material comprises one or more thermoplasticmaterials, one or more non-thermoplastic material, or a combination ofone or more thermoplastic materials and one or more non-thermoplasticmaterials. In some embodiments, the material is a polymer or aco-polymer.

In some embodiments, the material comprises a thermoplastic material. Insome embodiments, the material is a thermoplastic material. In someembodiments, the material is or comprises an erodible thermoplasticmaterial. In some embodiments, the thermoplastic material is edible(i.e., suitable for consumption by an individual). In some embodiments,the thermoplastic material is selected from the group consisting of ahydrophilic polymer, a hydrophobic polymer, a swellable polymer, anon-swellable polymer, a porous polymer, a non-porous polymer, anerodible polymer (such as a dissolvable polymer), a pH sensitivepolymer, a natural polymer, a wax-like material, and a combinationthereof. In some embodiments, the thermoplastic material is a celluloseether, a cellulose ester, an acrylic resin, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropyl cellulose,hydroxymethylcellulose, a mono- or diglyceride of C₁₂-C₃₀ fatty acid, aC₁₂-C₃₀ fatty alcohol, a wax, poly(meth)acrylic acid, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer57/30/13, polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) andpolyvinylpyrrolidone (PVP) 80/20, vinylpyrrolidone-vinyl acetatecopolymer (VA64), polyethylene glycol-polyvinyl alcohol graft copolymer25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA orPV—OH), poly(vinyl acetate) (PVAc), poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1, poly(dimethylaminoethylmethacrylate-co-methacrylicesters), poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride),poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1,poly(methacrylic acid-co-methylmethacrylate) 1:2, poly(methacylicacid-co-ethyl acrylate) 1:1, poly(methacylic acid-co-methylmethacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol)(PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulosephthalate, hypromellose phthalate, hydroxypropyl methylcellulose orhypromellose (HMPC), hydroxypropyl methylcellulose acetate succinate orhypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide)(PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinylacetate copolymer, polyethylene (PE), and polycaprolactone (PCL),hydroxyl propyl cellulose (HPC), polyoxyl 40 hydrogenerated castor oil,methyl cellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropylmethylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil,hydrogenated soybean oil, glyceryl palmitostearate, carnauba wax,polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetatebutyrate (CAB), polyvinyl acetate phthalate (PVAP), a wax, beeswax,hydrogel, gelatin, hydrogenated vegetable oil, polyvinyl acetal diethylaminolactate (AEA), paraffin, shellac, sodium alginate, celluloseacetate phthalate (CAP), arabic gum, xanthan gum, glyceryl monostearate,octadecanoic acid, thermoplastic starch, derivatives thereof (such asthe salts, amides, or esters thereof), or a combination thereof.

In some embodiments, the erodible material comprises a non-thermoplasticmaterial. In some embodiments, the erodible material is anon-thermoplastic material. In some embodiments, the non-thermoplasticmaterial is a non-thermoplastic starch, sodium starch glycolate(CMS-Na), sucrose, dextrin, lactose, microcrystalline cellulose (MCC),mannitol, magnesium stearate (MS), powdered silica gel, titaniumdioxide, glycerin, syrup, lecithin, soybean oil, tea oil, ethanol,propylene glycol, glycerol, Tween, an animal fat, a silicone oil, cacaobutter, fatty acid glycerides, vaseline, chitosan, cetyl alcohol,stearyl alcohol, polymethacrylate, non-toxic polyvinyl chloride,polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, or acombination thereof.

Exemplary materials that may be used with the device described herein orthe methods described herein include, but are not limited to, apoly(meth)acrylate co-polymer (such as a co-polymer containing one ormore of amino alkyl methacrylate, methacrylic acid, metacrylic ester,and/or ammonioalkyl methacrylate, such as a copolymer sold under thebrand name Eudragit® RSPO) and hydroxyl propyl cellulose (HPC).

In some embodiments, the material comprises a drug. In some embodiments,the material is admixed with a drug.

The material can be pressurized in the material control system using apressure controller. Material is loaded into a barrel, and the pressurecontroller can apply pressure to the material contained within thebarrel. The pressure controller can be a motor (such as a steppermotor), a valve, or any other suitable control device that operates, forexample, a piston, a pressure screw, or compressed air (i.e., apneumatic controller) that can apply force to the material containedwithin the barrel. The barrel includes one or more heaters that can meltthe material loaded into the heater. In some embodiments, the heater ispositioned within the barrel. In some embodiments, the heater ispositioned on the side or surrounding the barrel. In some embodiments,the heater is an electric radiant heater, for example an electricheating tube or coil. The barrel heater is preferably a powerful heaterwith a high voltage and high power output. In some embodiments, thebarrel heater has a voltage rating between 110V and 600V. In someembodiments, the barrel heater has a voltage rating between 210V and240V. In some embodiments, the barrel heater is a 220V heater. In someembodiments, the barrel heater has a wattage output between about 30 Wand about 100 W, such as between 40 W and 80 W, or about 60 W. In someembodiments, the heater is an electric heating coil that surrounds theoutside of the barrel. Preferably, the barrel is made from aheat-resistant material, such as stainless steel (for example 316Lstainless steel).

The material supply system includes a feed channel that connects thebarrel to the nozzle within the printing head. Material melting orsoftened within the barrel flows through the feed channel and to theprinting head. In some embodiments, one or more heaters are positionedwithin, around, or adjacent to the feed channel or a portion of the feedchannel (such as a lateral portion of the feed channel). The one or moreheaters are configured to heat material within the feed channel. In someembodiments, the heater is an electric radiant heater, for example anelectric heating tube or coil. For example, in some embodiments, anelectric heating tube is positioned along the length of the feed channelor at least a portion of the length of the feed channel. The heater ispreferably a powerful heater with a high voltage and high power output.In some embodiments, the feed channel heater has a voltage ratingbetween 110V and 600V. In some embodiments, the feed channel heater hasa voltage rating between 210V and 240V. In some embodiments, the feedchannel heater is a 220V heater. In some embodiments, the feed channelheater has a wattage output between about 30 W and about 100 W, such asbetween 40 W and 80 W, or about 60 W. In some embodiments, the deviceincludes one or more temperature sensors positioned adjacent to orwithin the feed channel, which is configured to measure the temperatureof the material within the feed channel. The feed channel is relativelywide compared to the extrusion port of the nozzle. In some embodiments,the feed channel has a diameter between about 1 mm and about 15 mm, suchas between about 1 mm and about 5 mm, between about 5 mm and about 10mm, or between about 10 mm and about 15 mm. In an exemplary embodiment,the feed channel has a diameter of about 8 mm.

The printing head of the device includes a nozzle, which includes anextrusion port through which melted material is extruded. The extrusionport is at the distal end of the nozzle relative to the feed channel.When the sealing needle is in the open position (including openpositions with various opening distances, e.g., a maximum openposition), melted material flows from the feed channel through thenozzle and out the extrusion port. The nozzle includes a tapered innersurface, with the extrusion port proximal to the vertex of the taperedinner surface. In some embodiments, the inner surface of the nozzleincludes a pad or a liner. The pad or liner can be made frompolytetrafluoroethylene (PTFE) or any other suitable material. In someembodiments, the printing head includes one or more heaters, which maybe positioned within, around, or adjacent to the nozzle of the printinghead. The one or more heaters are configured to heat material within thenozzle, which may be to the same temperature or a different temperatureas the material in the barrel or the feed channel. In some embodiments,the nozzle heater is an electric radiant heater, for example an electricheating tube or coil. The heater may be a lower voltage and/or lowerwattage heater than the barrel heater or the feed channel heater. Insome embodiments, the nozzle heater has a voltage rating between 6V and60V. In some embodiments, the nozzle heater is a 12V heater. In someembodiments, the nozzle heater has a wattage output between about 10 Wand about 60 W, such as between 20 W and 45 W, or about 30 W. In someembodiments, the printing head includes one or more temperature sensorspositioned adjacent to or within the nozzle, which is configured tomeasure the temperature of the material within the nozzle.

The device includes a pressure sensor configured to detect pressure ofthe material within the printing head or the feed channel proximal tothe printing head. In some embodiments, the pressure sensor is connectedto a computer system that operates the material supply system topressurize the material to a desired pressure in response to thepressure reported by the pressure sensor. For example, the computersystem can operate the pressure controller to adjust the amount ofpressure exerted on the material within the barrel. In some embodiments,the system operates as a closed-loop feedback system to maintain anapproximately constant pressure within the device. In some embodiments,the feedback system is operated using a proportional-integral-derivative(PID) controller, a bang-bang controller, a predictive controller, afuzzy control system, an expert system controller, or any other suitablealgorithm. In some embodiments, the pressure sensor is precise within0.005 MPa, within 0.008 MPa, within 0.05 MPa, within 0.1 MPa, within 0.2MPa, within 0.5 MPa, or within 1 MPa. In some embodiments, the samplerate of the pressure sensor is about 20 ms or less, such as about 10 msor less, about 5 ms or less, or about 2 ms or less. In some embodiments,the pressure of the material within about 0.005 MPa, about 0.008 MPa,about 0.05 MPa, about 0.1 MPa, about 0.2 MPa, about 0.5 MPa, or about 1MPa of the desired pressure.

In some embodiments, the device includes one or more temperaturesensors. In some embodiments, the device includes a temperature sensorpositioned within or adjacent to the barrel or configured to detecttemperature within the barrel. In some embodiments, the device includesa temperature sensor positioned within or adjacent to the feed channelor configured to detect temperature within the feed channel. In someembodiments, the device includes a temperature sensor positioned withinor adjacent to the printing head or configured to detect temperaturewithin the nozzle. In some embodiments, the one or more temperaturesensors are connected to a computer system that operates the one or moreheaters in response to a temperature reported by the one or moretemperature sensors. For example, the computer system can operate theone or more heaters to adjust the temperature of the material within thebarrel, feed channel, and/or nozzle. In some embodiments, the systemoperates as a closed-loop feedback system to maintain an approximatelyconstant temperature within the device or a component of the device(i.e., the barrel, nozzle, or feed channel). The temperature of thematerial within different components of the device may be the same ordifferent. In some embodiments, the feedback system is operated using aproportional-integral-derivative (PID) controller, a bang-bangcontroller, a predictive controller, a fuzzy control system, an expertsystem controller, or any other suitable algorithm.

The device described herein includes a control switch. The controlswitch can be operated to prevent or allow melted material to flow fromthe extrusion port of the device. The control switch includes a sealingneedle operable in an open position (including open positions withvarious opening distances, e.g., a maximum open position) and a closedposition, wherein material flow through the nozzle is inhibited with thesealing needle is in the closed position. The sealing needle extendsthrough at least a portion of the feed channel and includes a taperedend. When the sealing needle is in the closed position, the tapered endof the sealing needle engages the tapered inner surface of the nozzle(for example, at the extrusion port of the nozzle).

The “opening distance” of the sealing needle valve described hereinrefers to the distance (D_(open)) between the position of the taperedend (e.g., tip of the tapered end) when the sealing needle is in an openposition (hereinafter referred to as position d_(x)) and the position ofthe tapered end when the sealing needle is in its closed position thatcompletely seals the extrusion port of the nozzle (hereinafter referredto as position d₀), i.e., D_(open)=d_(x)−d₀. The movement of the sealingneedle, or the distance D_(open), can be controlled via an actuatorwithin the control switch, such as an electric motor actuator (e.g.,linear stepper motor actuator), thus modulating the amount and/or speedof material extrusion from the nozzle. By measuring the amount ofmaterial extrusion (e.g., average amount of material extrusion, in mg)from the nozzle and the corresponding distance D_(open) (e.g., in mm), aplot of opening distance of the sealing needle valve (x-axis) vs.material extrusion amount (y-axis) can be obtained. In some embodiments,when the pressure of the material within the printing head or the feedchannel proximal to the printing head is at a constant value, the amount(e.g., average amount) of material extrusion increases along with theincrease of the opening distance of the sealing needle valve; whenmaximum material extrusion amount (e.g., average amount) is reached, theamount (e.g., average amount) of material extrusion remains at a fairlysteady value despite of the further increase of the opening distance ofthe sealing needle valve. In some embodiments, when the pressure of thematerial within the printing head or the feed channel proximal to theprinting head is about 0.4 MPa, the maximum material extrusion amount(e.g., average amount) is reached when the opening distance of thesealing needle valve is more than about 0.8 mm. In some embodiments, therelationship between the maximum material extrusion amount (e.g.,average amount) and the opening distance of the sealing needle valve canbe affected by factors such as the printing material, printingtemperature, diameter of the nozzle and/or the sealing needle, shape ofthe nozzle and/or the sealing needle, material of the nozzle and/or thesealing needle, pressure of the material, moving speed of the sealingneedle, etc.

In some embodiments, the sealing needle can be positioned in an openposition with an opening distance up to about 5 mm, such as up to about4 mm, up to about 3 mm, up to about 2 mm, up to about 1.5 mm, up toabout 1.4 mm, up to about 1.3 mm, up to about 1.2 mm, up to about 1.1mm, up to about 1.0 mm, up to about 0.9 mm, up to about 0.8 mm, up toabout 0.7 mm, up to about 0.6 mm, up to about 0.5 mm, up to about 0.4mm, up to about 0.3 mm, up to about 0.2 mm, or up to about 0.1 mm. Insome embodiments, the sealing needle can be positioned in an openposition with an opening distance of about 0.1 mm to about 2.0 mm, about0.2 mm to about 1.6 mm, about 0.4 mm to about 1.2 mm, about 0.4 mm toabout 1.0 mm, about 0.4 mm to about 0.9 mm, about 0.4 mm to about 0.8mm, about 0.4 mm to about 0.7 mm, about 0.4 mm to about 0.6 mm, about0.7 mm to about 1.1 mm, about 0.7 mm to about 1.0 mm, about 0.7 mm toabout 0.9 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm,about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 0.89 mm,about 0.88 mm, about 0.87 mm, about 0.86 mm, about 0.85 mm, about 0.84mm, about 0.83 mm, about 0.82 mm, about 0.81 mm, about 0.79 mm, about0.78 mm, about 0.77 mm, about 0.76 mm, or about 0.75 mm.

In some embodiments, any portion of the sealing needle that contacts thematerial is free of protrusions. A protrusion can be any portion of thesealing needle that has a diameter larger than the sealing needle shaft,or any member of the sealing needle that extends outward further thanthe sealing needle shaft. A protrusion on the sealing needle can pushmelted material through the extrusion port upon positioning the sealingneedle in the closed position, and is preferably avoided. In someembodiments, the entire sealing needle (whether or not the sealingneedle contacts the material) is free of protrusions. In someembodiments, the portion of the sealing needle that does not contact thematerial comprises one or more protrusions, which may, for example,engage a component of the actuator or act as a depth break to preventthe sealing needle from being driven too far within the feed chamber.

The portion of the sealing needle that contacts the material (that is,the portion that is positioned within the feed channel when the sealingneedle is in the open position (including open positions with variousopening distances, e.g., a maximum open position) or the closedposition) is relatively thin compared to the feed channel, which allowsthe melted material to flow around the sealing needle rather than beingpushed down and out the extrusion port. In some embodiments, the portionof the sealing needle that contacts the material has a largest diameterof about 0.2 mm to about 3.0 mm, such as about 0.2 mm to about 0.5 mm,about 0.5 mm to about 1.0 mm, about 1.0 mm to about 1.5 mm, about 1.5 mmto about 2.0 mm, about 2.0 mm to about 2.5 mm, or about 2.5 mm to about3.0 mm. In some embodiments, the sealing needle (including the portionof the sealing needle that contacts the material and the portion of thesealing needle that does not contact the material) has a largestdiameter of about 0.2 mm to about 3.0 mm, such as about 0.2 mm to about0.5 mm, about 0.5 mm to about 1.0 mm, about 1.0 mm to about 1.5 mm,about 1.5 mm to about 2.0 mm, about 2.0 mm to about 2.5 mm, or about 2.5mm to about 3.0 mm.

In some embodiments, the sealing needle comprises a pointed tip at thetapered end, as shown in FIG. 3A. In some embodiment, the tapered end ofthe tip is frustoconical, as shown in FIG. 3B. Both the nozzle and thesealing needle include tapered surfaces such that the tapered end of thesealing needle is directed into the tapered inner surface of the nozzle.The “taper angle” as used herein refers to the angle of the vertex ofthe joining surface. In the instance of a frustoconical tapered tip, the“taper angle” refers to the vertex of the extrapolated joining surface.The taper angle of the tapered end of the sealing needle is indicated byα in FIG. 3A and FIG. 3B, and the taper angle of the nozzle is indicatedby β in the nozzle illustrated in FIG. 3C. In some embodiments, thetaper angle of the tapered end of the sealing needle is about 60° orless, such as about 50° or less, 45° or less, 40° or less, 35° or less,30° or less, 25° or less, 20° or less, or 15° or less. In someembodiments, the taper angle of the sealing needle (α) is the same orsmaller than the taper angle of the inner surface of the nozzle (β). Insome embodiments, the ratio of the taper angle of the inner surface ofthe nozzle (β) to the taper angle of the sealing needle (a) to is about1:1 to about 4:1, or about 1:1 to about 3:1, or about 1:1 to about 2:1.

The sealing needle is positioned in the closed position by lowering thesealing needle towards the extrusion port, which is aligned with thesealing needle. Pressurized and melted material can flow through theextrusion port when the sealing needle is in the open position(including open positions with various opening distances, e.g., amaximum open position), but is prevented from flowing when the sealingneedle is in the closed position, where it engages the inner surface ofthe nozzle. When the taper angle of the inner surface of the nozzle (β)is wider than the taper angle of the sealing needle (α), the tapered endof the sealing needle engages the inner surface of the nozzle at thepoint of the extrusion port. In some embodiments, the extrusion port hasa diameter of about 0.1 mm or more, such as about 0.15 mm or more, about0.25 mm or more, about 0.5 mm or more, or about 0.75 mm or more. In someembodiments, the extrusion port has a diameter of about 1 mm or less,such as about 0.75 mm or less, about 0.5 mm or less, about 0.25 mm orless, or about 0.15 mm or less. The sealing needle, including the baseof the tapered end of the sealing needle, is preferably thin to limitmelted material from being pushed through the extrusion port when thesealing needle is positioned in the closed position. In someembodiments, the ratio of the largest diameter of the tapered end of thesealing needle (i.e., the base of the taper) to the diameter of theextrusion port is about 1:0.8 to about 1:0.1, such as about 1:0.8 toabout 1:0.7, about 1:0.7 to about 1:0.6, about 1:0.6 to about 1:0.5,about 1:0.5 to about 1:0.4, about 1:0.4 to about 1:0.3, about 1:0.3 toabout 1:0.2, or about 1:0.2 to about 1:0.1.

The sealing needle preferably comprises a strong yet flexible material.Exemplary materials include, but are not limited to, stainless steel,polytetrafluoroethylene (PTFE), and carbon fiber. In some embodiments,the inner surface of the nozzle comprises a flexible pad or liner, whichcan limit damage to the needle or nozzle upon repeated repositioning ofthe sealing needle in the open position or closed position. In someembodiments, the pad or liner is made from polytetrafluoroethylene(PTFE).

The sealing needle of the control switch is operated using an actuatorthat can position the sealing needle in an open position (i.e., byraising the sealing needle such that the tapered end of the sealingneedle no longer engages the inner surface of the nozzle, including openpositions with various opening distances, e.g., a maximum open position)or a closed position (i.e., by lowering the sealing needle such that thetapered end of the sealing needle engages the inner surface of thenozzle). In some embodiments, the actuator is a linear actuator. In someembodiments, the actuator is a pneumatic actuator, which can becontrolled using air pressure within the actuator. In some embodiments,the actuator is a mechanical actuator, which can raise or lower thesealing needle through the use of one or more gears and a motor. In someembodiments, the actuator is a hydraulic actuator. In some embodiments,the actuator is an electric motor actuator, such as a linear steppermotor actuator, or torque actuator. In some embodiments, the actuatorincludes an electromagnetic valve or an electrostrictive polymer.

FIG. 2A illustrates a cross-sectional view of an exemplary device fordepositing a material by additive manufacturing according to the presentinvention. Material can be loaded into a barrel 202 of the materialsupply system, and a piston 204 applies pressure to the material bypushing into the barrel 202. The piston 204 is connected to a pressurecontroller through a guide arm 206. The piston 204 is lowered by amotor, such as a stepper motor, to increase pressure of the material inthe barrel 202, or is raised to lower pressure of the material. Thematerial in the barrel 202 can be heated to or above a meltingtemperature of the material using a heater within or surrounding thebarrel. Melted material from the barrel 202 flows through a feed channel208, which joins to a printing head 210 that includes a nozzle 212. Apressure sensor 214 is positioned at the end of the feed channel 208proximal to the printing head 210, and is configured to detect pressureof the material proximal to the printing head. In some embodiments, thepressure sensor 214 is positioned to detect pressure of the materialwithin the printing head 210. The pressure sensor 214 can transmit thedetected pressure to a computer system, which can operate the pressurecontroller (or motor of the pressure controller) to reposition thepiston 204 and control pressure of the material within the barrel 202.This can operate in a feedback system, wherein the change of pressure isthen detected by the pressure sensor 214, and the computer systemfurther operates the pressure controller.

The device includes a control switch 216, which includes a sealingneedle 218 and a linear actuator 220. The sealing needle 218 includes anupper end 222 that engages the actuator 220, and a lower end 224 that istapered. The sealing needle 218 extends through the feed channel 208into the printing head 210. The actuator 220 operates the sealing needle218 between an open position (raised) and a closed position (lowered).When the sealing needle 218 is positioned in a closed position, thetapered end 224 of the sealing needle 218 engages the tapered innersurface of the nozzle 212 to inhibit flow of melted material through thenozzle. To open the nozzle 212 and allow melted material to flow throughthe extrusion port, the actuator 220 operates the sealing needle 218 toposition the sealing needle 218 in an open position by raising thesealing needle 218, thereby disengaging the tapered lower end 224 fromthe inner surface of the nozzle 212. FIG. 2B illustrates a zoomed inview of the printing head 210 with the sealing needle 218 in the closedposition and engaging the nozzle 212. In the closed position, thetapered end 224 of the sealing needle 218 plugs the extrusion port 226by engaging the tapered inner surface of the nozzle 212. Melted materialin the feed channel 208 is therefore prevented from flowing through theextrusion port 226 by the tapered end 224 of the sealing needle.Pressure of the material within or proximal to the printing head 210 isdetected by the pressure sensor 214, and the pressure controller can beoperated to prevent excess pressure buildup in the device when thesealing needle 218 is in the closed position.

The sealing needle 218 extends through the feed channel 208 and into theprinting head 210. When the sealing needle 218 is positioned from theopen position to the closed position, careful design prevents meltedmaterial in the feed channel 208 from being pushed out of the extrusionport 226 by the sealing needle 218. The tapered end 224 of the sealingneedle 218 allows the sealing needle 218 to pierce the melted material,allowing the melted material to flow up and around the closing sealingneedle 218 instead of being pushed down.

The pneumatic actuator 220 includes an electromagnetic valve that isused to control the flow of gas into an air chamber 226, which can driveup or down a central rod 228 attached to the upper end 222 of thesealing needle 218. High pressure gas that flows into the air chamber226 from below the diaphragm 230, or removal of gas from above thediaphragm 230, causes the diaphragm 230 to move upwardly, whichpositions the sealing needle 218 in the open position. Removing the gasfrom below the diaphragm 230 or applying high pressure gas above thediaphragm 230 causes the diaphragm 230 to move downwardly, whichpositions the sealing needle 218 in the closed position.

Although the device in FIG. 2A includes a pneumatic actuator, otherlinear actuators may be used. For example, the actuator can be anelectric motor actuator, such as a linear stepper motor actuator.Similarly, the linear stepper motor actuator may move the central rod228 attached to the upper end 222 of the sealing needle 218 eitherupwardly which positions the sealing needle 218 in the open position(including open positions with various opening distances, e.g., amaximum open position), or downwardly, which positions the sealingneedle 218 in the closed position. Further, the linear stepper motoractuator may provide more precise control of the opening distance of thesealing needle valve in order to modulate the amount and flow speed ofmaterial extrusion from the nozzle.

FIG. 4 illustrates an exploded view of components of the pneumaticactuator that connect to the sealing needle to control the sealingneedle. The diaphragm 402 is positioned within the air chamber of thepneumatic actuator, and is connected to a central rod 404, for examplethrough a threaded fit. The central rod 404 is connected to an adapter406, for example by a threaded fit. The adapter 406 attaches to thesealing needle 408, for example by a threaded fit or by a force fit. Forexample, the lower part of the adapter 406 can include an opening, andthe upper portion of the sealing needle 408 can be snugly fit into theopening by jamming the sealing needle 408 into the opening of theadapter 406. The sealing needle 408 passes through a gasket 410, whichis held in place by a fixing nut 412. The fixing nut 412 is attached tothe rest of the device through a manifold block, which holds the fixingnut 412 and gasket in place. Referring to FIG. 2A, the manifold block232 is positioned above the feed channel 208 in line with the nozzle 212of the printing head 210. A manifold block channel 234 passes throughthe manifold block 232 to access the feed channel. The gasket 236 fitsinto an opening towards the top of the manifold block 232, which iswider than the channel 234, thereby preventing the gasket 236 frommoving toward the printing head 210. The gasket 236 can be made from aninert pliable material, such as a plastic or synthetic rubber, and sealsthe feed channel 208 to prevent leakage of the melted material flowingin from the feed channel 208. In some embodiments, the gasket comprisespolytetrafluoroethylene (PTFE). A fixing nut 238 is secured to themanifold block 232, for example by a threaded fit, and secures theposition of the gasket 236. Accordingly, the gasket 236 is in a fixedposition relative to the printing head 210 and nozzle 212. The sealingneedle 218 passes through a hole in the fixing nut 238 and the gasket236 to reach the feed channel 208. The hole is sized to allow the needleto pass through and move as controlled by the actuator 220, but is notso large that it allows leakage of melted material.

The material supply system includes one or more heaters that meltmaterial contained therein. The heaters can be positioned around orwithin the barrel that contains the material, the feed channel, and/orthe printing head of the device. FIG. 5A shows a longitudinal sectionview of a portion of the exemplary device, with FIG. 5B showing across-sectional view at plane “A-A,” and FIG. 5C showing a non-crosssectional view of the device. A pneumatic actuator is used in thisexemplary device. In some embodiments, the device includes a heater 502surrounding the barrel 504 of the device, which can heat and meltmaterial contained within the barrel 504. The heater 502 can be, forexample, a coil heater that surrounds the outside of the barrel 504. Insome embodiments, the heater is disposed within the barrel. Materialplaced within the barrel is initially melted within the barrel by theheater, and pressure is applied to the material by the piston 506.Melted material then flows from the barrel 504 to the feed channel 508.In some embodiments, to ensure the material in the feed channel 508remains melted at the desired temperature, one or more heaters can bepositioned adjacent to or within the feed channel 508. FIG. 5B and FIG.5C illustrate two heaters 510 a and 510 b, each positioned adjacent tothe feed channel 508 on opposite sides of the feed channel 508. In someembodiments, the heaters 510 a and/or 510 b span the length of the feedchannel 508 or span the length of the lateral portion of the feedchannel 508. In some embodiments, the one or more heaters adjacent to orwithin the feed channel 508 is a heating rod. In some embodiments, theone or more heaters adjacent to or within the feed channel 508 is a coilthat surrounds the feed channel 508. The one or more heaters that heatthe material within the feed channel 508 ensures that that the materialremains melted and has the correct viscosity for predictable flow for agiven applied pressure. In some embodiments, the printing head 512 ofthe device includes one or more heaters 514, which ensures the materialremains melted and at the correct viscosity within the nozzle 516.

In some embodiments, the device includes one or more temperaturesensors, which may be positioned at one or more locations within thedevice and can detect the temperature of the material within the device,such as within the barrel, the feed channel or the printing head. Theembodiment illustrated by FIGS. 5A-5C include a first temperature sensor518 adjacent to the feed channel 508, and a second temperature sensor520 adjacent to the printing head 512. The temperature sensor 518adjacent to the feed channel 508 is illustrated at the start of thelateral portion of the feed channel 508, but the temperature sensor 518can optionally be positioned anywhere along the length of the feedchannel 508. The temperature sensor 518 and the one or more heaters(e.g., 510 a and 510 b) positioned to heat and/or melt material withinthe feed channel 508 can be operated in a closed-loop feedback system,which can ensure approximately constant temperature of the materialwithin the feed channel. For example, the temperature sensor 518 cantransmit a measured temperature to a computer system, and the computersystem can operate the one or more heaters 510 a and 510 b to ensure anapproximately constant temperature. The temperature sensor 520 in theprinting head 512 of the device can operate with the one or more heaters514 in the printing head in a closed-loop feedback system to ensureapproximately constant temperature of the material within the printinghead. The feedback system can be operated using aproportional-integral-derivative (PID) controller, a bang-bangcontroller, a predictive controller, a fuzzy control system, an expertsystem controller, or any other suitable algorithm. In some embodiments,the one or more heaters in the device heat the material within thesystem to a temperature at or above the melting temperature of thematerial. In some embodiments, the one or more heaters heats thematerial to a temperature of about 60° C. or higher, such as about 70°C. or higher, 80° C. or higher, 100° C. or higher, 120° C. or higher,150° C. or higher, 200° C. or higher, or 250° C. or higher. In someembodiments, the one or more heaters heats the material to a temperatureof about 300° C. or lower, such as about 260° C. or lower, 200° C. orlower, 150° C. or lower, 100° C. or lower, or 80° C. or lower. In someembodiments, the one or more heaters heat the material to differenttemperatures at different locations of the device. For example, in someembodiments, the material is heated to a first temperature within thebarrel, a second temperature within the feed channel, and a thirdtemperature within the printing head, each of which may the sametemperature or different temperatures. By way of example, a material maybe heated to 140° C. in the barrel and the feed channel, but to 160° C.when in the printing head. The feedback control system allows highprecision of the temperature. In some embodiments, the temperature iscontrolled within 0.1° C. of the target temperature, within 0.2° C. ofthe target temperature, within 0.5° C. of the target temperature, orwithin 1° C. of the target temperature.

The device includes one or more pressure sensors, which can detectpressure of the material within the device. In some embodiments, thepressure sensor is configured to detect pressure of the material withinthe printing head or the feed channel proximal to the printing head. Insome embodiments, the pressure sensor is positioned within the printinghead or adjacent to the feed channel and proximal to the printing head.The pressure sensor can operate with the pressure controller in aclosed-loop feedback system to provide approximately constant pressureto the material in the device. For example, when the pressure sensordetects a decrease in pressure, feedback system can signal the pressurecontroller to increase pressure of the material (e.g., by lowering thepiston, increasing air pressure in the barrel, turning the pressurescrew, etc.). Similarly, when the pressure sensor detects an increase inpressure, the feedback system can signal the pressure controller todecrease pressure of the material (e.g., by raising the piston,decreasing air pressure in the barrel, turning the pressure screw,etc.). Constant pressure ensures that the melted material in the deviceis extruded through the extrusion port of the nozzle at a constant ratewhen the sealing needle is in the open position (including openpositions with various opening distances, e.g., a maximum openposition). However, when the sealing needle is in a closed position,constant pressure increase (e.g., by lowering the piston, increasing airpressure in the barrel, turning the pressure screw, etc.) may causeleakage of the melted material through the nozzle. Additionally, thefeedback system including the pressure sensor and pressure controllerkeeps an approximately constant pressure in the system when the sealingneedle is repositioned from the open position (including open positionswith various opening distances, e.g., a maximum open position) to theclosed position, or from the closed position to the open position(including open positions with various opening distances, e.g., amaximum open position). This minimizes a “ramp up” in extrusion ratewhen the sealing needle is positioned in the open position (includingopen positions with various opening distances, e.g., a maximum openposition) from the closed position because there is no need to ramp uppressure of the material in the system. In some embodiments, thepressure sensor detects pressure changes within the printing head whilethe opening distances of the sealing needle valve change, and transmitssignals to the device to control the open position of the sealing needlevia a closed-loop feedback system to synchronize with printing speed(such as according to the printing instruction of a product). Thefeedback system can be operated using a proportional-integral-derivative(PID) controller, a bang-bang controller, a predictive controller, afuzzy control system, an expert system controller, or any other suitablealgorithm. In some embodiments, the sample rate of the pressure sensoris about 20 ms or less, such as about 10 ms or less, about 5 ms or less,or about 2 ms or less. In some embodiments, the pressure is controlledwithin 0.05 MPa of the target pressure, within 0.1 MPa of the targetpressure, within 0.2 MPa of the target pressure, within 0.5 MPa of thetarget pressure, or within 1 MPa of the target pressure.

FIG. 6 illustrates another example of a device as described herein.Material is loaded into a barrel 602 of the material supply system, anda pressure screw 604 (i.e., a screw piston) can apply pressure to thematerial in the barrel 602. To increase pressure to the material, apressure controller 608 (e.g., a stepper motor) turns a first gear 610,which turns a second gear 612 connected to the pressure screw 604. Thematerial in the barrel 602 can be heated by a heater 614 surrounding thebarrel. Melted material from within the barrel 602 flows through a feedchannel 616 to a printing head 618, which includes a nozzle 620. Thedevice can include a pressure sensor 630, which is configured to detectpressure of the material in the barrel 602, the feed channel 616, and/orthe printing head 618. The pressure sensor 630 can transmit the detectedpressure to a computer system, which can operate the pressure controller608 to reposition the pressure screw 604 and control pressure of thematerial within the barrel 602. This can operate in a feedback system,wherein the change of pressure is then detected by the pressure sensor630, and the computer system further operates the pressure controller.The exemplary device illustrated in FIG. 6 includes a control switch,which includes a sealing needle 622 along the same axis as the barrel602, and an actuator 624. The sealing needle 622 includes an upper endthat joins to the actuator 624, and a lower tapered end (not shown). Theactuator 624 operates the sealing needle 622 between an open position(raised, including open positions with various opening distances, e.g.,a maximum open position) and a closed position (lowered). When thesealing needle 622 is positioned in a closed position, the tapered endof the sealing needle 622 engages the tapered inner surface of thenozzle 620 to inhibit flow of melted material through the nozzle. Theprinting head 618 can also include one or more heaters 626 and atemperature sensor 628, which can operate in a feedback system.

In certain embodiments, there is an additive manufacturing system thatincludes a plurality (e.g., two or more, three or more, four or more,five or more, or six or more) of devices as described herein, whichincludes a material supply system configured with a control switch(including a sealing needle with a tapered end operable in an openposition (including open positions with various opening distances, e.g.,a maximum open position) and a closed position and an actuator). In someembodiments, at least two of the devices from the plurality of devicescomprise a material supply system configured to melt and pressurize thematerial, comprising a feed channel connected to a printing headcomprising a nozzle, the nozzle comprising a tapered inner surface andan extrusion port configured to dispense the material; a pressure sensorconfigured to detect a pressure of the material within the nozzle or thefeed channel proximal to the nozzle; and a control switch comprising asealing needle operable in an open position and a closed position, thesealing needle extending through a portion of the feed channel andcomprising a tapered end; and wherein the tapered end of the sealingneedle engages the tapered inner surface of the nozzle to inhibitmaterial flow through the nozzle when the sealing needle is in theclosed position. In some embodiments, the tapered inner surface of thenozzle has a first taper angle and the tapered end of the sealing needlehas a second taper angle; and wherein the second taper angle is the sameor smaller than the first taper angle. In some embodiments, the controlswitch of each device within the system is different. In someembodiments, the control switches of some devices are the same, butdifferent from that of other devices within the system. For example, insome embodiments, the actuator (such as linear actuator, e.g., pneumaticactuator, linear stepper motor actuator) of each control switch is thesame, but the configured sealing needles are different (e.g., differentdiameters). In some embodiments, the actuator (such as linear actuator)of each control switch is different (e.g., one device comprisespneumatic actuator, the other device comprises electric motor actuator),but the sealing needles are the same. In some embodiments, the actuators(such as linear actuator) and the configured sealing needles are alldifferent among different devices of the system. In some embodiments,the control switches of all devices within the system are the same(e.g., same electric motor actuator configured with the same sealingneedle). The material in each of the separate devices may be the same ordifferent. For example, in some embodiments, the system comprises twodevices and two different materials (i.e., a first material and a secondmaterial). In some embodiments, the system comprises three devices andthree different materials (i.e., a first material, a second material,and a third material). In some embodiments, the system comprises fourdevices and four different materials (i.e., a first material, a secondmaterial, a third material and a fourth material). In some embodiments,the system comprises five devices and five different materials (i.e., afirst material, a second material, a third material, a fourth material,and a fifth material). In some embodiments, the system comprises sixdevices and six different materials (i.e., a first material, a secondmaterial, a third material, a fourth material, a fifth material, and asixth material). In some embodiments, the additive manufacturing systemincludes a first device loaded with a first material, and a seconddevice loaded with a second material, wherein the first material and thesecond material are different. The different material supply systems inthe additive manufacturing system can extrude different materials toform a multi-component printed product, such as a multi-componentpharmaceutical dosage form (such as a tablet). When one of the materialsupply systems is active (i.e., the sealing needle is in the openposition (including open positions with various opening distances, e.g.,a maximum open position)), the other material supply systems in thedevice are inactive (i.e., the sealing needle is in the closedposition). The device can quickly transition between active materialsupply systems by coordinating the positon of the sealing needles ineither the open position (including open positions with various openingdistances, e.g., a maximum open position) or the closed position. FIG. 7illustrates a portion of an exemplary system that includes threematerial supply systems, each with a distinct printing head 702, 704,and 706. The printing table 708 is movable in the x-, y-, andz-dimensions to position the resulting product under the correctprinting head, which can extrude material to produce a product 710 (suchas a pharmaceutical tablet).

In some embodiments, the device (or system comprising a plurality ofdevices) described herein is connected to a computer system, which canoperate any one or more of the various components of the device. Forexample, in some embodiments, the computer system operates the one ormore heaters, the pressure controller, and/or the control switch. Insome embodiments, the computer system operates the one or more heatersin response to a temperature detected by the one or more temperaturesensors (i.e., in a feedback control). In some embodiments, the computersystem operates the pressure controller in response to a pressuredetected by the one or more pressure sensors. In some embodiments, thecomputer system operates the control switch in response to theinstructions for printing the product, to switch the sealing needlebetween an open position (including open positions with various openingdistances, e.g., a maximum open position) and a closed position, as wellas control the opening distances of the sealing needle valve. In someembodiments, the computer system coordinates the transition betweenactive material supply systems among multiple devices in response to theinstructions for printing the product. The computer system includes oneor more processors and a computer readable memory, which can includeinstructions for operating the device (or system comprising a pluralityof devices), such as instructions for controlling the open position(including open positions with various opening distances, e.g., amaximum open position) and a closed position of each sealing needlewithin each device, and/or the opening distances of the sealing needlevalve of each device, by controlling the actuator (such as linearactuator, e.g., pneumatic actuator, linear stepper motor actuator) ofeach device. In some embodiments, the computer system is a desktopcomputer, a laptop computer, a mobile device (such as a mobile phone ortablet), a programmable logic controller (PLC), or a microcontroller.The computer system may include, for example, a processor, memory,storage, and input/output devices (e.g., monitor, keyboard, disk drive,Internet connection, etc.). However, computing system may also includecircuitry or other specialized hardware for carrying out some or allaspects of the methods described herein and/or for operating the devicesand systems described herein. In some operational settings, computingsystem may be configured as a system that includes one or more units,each of which is configured to carry out some aspects of the processeseither in software, hardware, or some combination thereof. The mainsystem of an exemplary computer system can include a motherboard havingan input/output (“I/O”) section, one or more central processing units(“CPU”), and a memory section, which may have a flash memory cardrelated to it. The I/O section can be connected to a display, akeyboard, a disk storage unit, a media drive unit, and/or one of thedevices or systems described herein. The media drive unit can read/writea computer-readable medium, which can contain programs (i.e.,instructions) and/or data. At least some values based on the results ofthe above-described processes can be saved for subsequent use.Additionally, a non-transitory computer-readable medium can be used tostore (e.g., tangibly embody) one or more computer programs forperforming any one of the above-described processes by means of acomputer. The computer program may be written, for example, in ageneral-purpose programming language (e.g., Pascal, C, C++, Java,Python, JSON, etc.) or some specialized application-specific language.

In some embodiments, the computer system comprises one or moreprocessors and a computer readable memory comprising instructions forprinting a product (such as a pharmaceutical dosage form, for example, atablet) by additive manufacturing. In some embodiments, the computersystem operates the control switch in response to the instructions forprinting the product. In some embodiments, the instructions for printingthe product include instructions for printing the product using alayer-by-layer extrusion method. In some embodiments, the computerreadable memory comprises instructions for controlling the open position(including open positions with various opening positions, e.g., amaximum open position) and closed position of each sealing needle withinthe device (or each device within a system), and/or the openingdistances of the sealing needle valve of the device (or each devicewithin a system), by controlling the actuator (such as linear actuator,e.g., pneumatic actuator, linear stepper motor actuator) of the device(or each device within a system). In some embodiments, the computerreadable memory comprises instructions for positioning the sealingneedle based on the instructions for printing the product. In someembodiments, the instructions for positioning the sealing needlecomprise instructions for selecting an opening distance of the sealingneedle based on a desired flow rate of the material from the extrusionport. In some embodiments, the instructions for positioning the sealingneedle is based on the signals transmitted from the pressure sensorwithin the printing head. For example, when the pressure within theprinting head is too high, and/or the instructions for printing theproduct requires slower printing speed, the computer readable memoryinstructs the opening distance of the sealing needle valve to decrease;when the pressure within the printing head is too low, and/or theinstructions for printing the product requires higher printing speed,the computer readable memory instructs the opening distance of thesealing needle valve to increase.

The instructions for printing a product, such as a pharmaceutical dosageform, may be generated using any one or more of different methods,including direct coding, derivation from a solid CAD model, or othermeans specific to the three-dimensional printing machine's computerinterface and application software. These instructions may includeinformation on the number and spatial placement of droplets, and ongeneral print parameters such as the drop spacing in each lineardimension (X, Y, Z), and volume or mass of fluid per droplet. For agiven set of materials, these parameters may be adjusted in order torefine the quality of structure created. The overall resolution of thestructure created is a function of the powder particle size, the fluiddroplet size, the print parameters, and the material properties.

A method of depositing a material or manufacturing a product by additivemanufacturing can include the steps of melting and pressurizing thematerial; flowing the material through an extrusion port of a nozzlecomprising a tapered inner surface; monitoring pressure of the materialwithin the nozzle or proximal to the nozzle; engaging a tapered end of asealing needle with the tapered inner surface of the nozzle, therebysealing the extrusion port and stopping flow of the melted material; andwithdrawing the tapered end of the sealing needle, thereby resuming flowof the material through the extrusion port. In some embodiments, themethod comprises withdrawing the tapered end of the sealing needle to aselected opening distance (e.g., a maximum open position). In someembodiments, the method is performed using a device as described herein.In some embodiments, the device includes a plurality of material supplysystems, wherein each material supply system is configured with acontrol switch. In some embodiments, the control switch configured toeach material supply system is the same. In some embodiments, thecontrol switch configured to each material supply system is different(e.g., by using different actuators or sealing needles of differentdiameters). The method can include dispensing a first material from afirst material supply system and dispensing a second material from asecond material supply system, wherein the sealing needle of the firstmaterial supply system is in the closed position when the secondmaterial is dispensed from the second material supply system, and thesealing needle of the second supply system is in the closed positionwhen the first material is dispensed from the first material supplysystem. In some embodiments, the method is performed in batch mode ofoperation. In some embodiments, the device or system is operated inbatch mode. The term “batch mode” refers to a mode of operation in whicha predetermined number of products (such as pharmaceutical dosage forms)are manufactured. In some embodiments, the method is performed in acontinuous mode of operation. In some embodiments, the device or systemis operated in continuous mode. The term “continuous mode” refers to amode of operation in which the device or system is operated for apredetermined period of time or until a predetermined amount of materialor materials have been used.

In some embodiments, a method of manufacturing a product by additivemanufacturing includes melting and pressurizing a first material;flowing the first material through a first extrusion port of a firstnozzle comprising a tapered inner surface; engaging a tapered end of afirst sealing needle with the tapered inner surface of the first nozzle,thereby sealing the first extrusion port and stopping flow of the meltedfirst material; melting and pressurizing a second material; andwithdrawing a tapered end of a second sealing needle from a taperedinner surface of a second nozzle, thereby initiating flow of the secondmaterial through a second extrusion port. In some embodiments, themethod comprises withdrawing the tapered end of the second sealingneedle to a selected opening distance (e.g., a maximum open position),which may adjust the amount and/or speed of the flow of the materialthrough the extrusion port. In some embodiments, the method comprisesreceiving instructions for manufacturing the product, for example from acomputer system.

In some embodiments, a method of manufacturing a pharmaceutical dosageform (such as a tablet) by additive manufacturing includes the steps ofmelting and pressurizing a pharmaceutically acceptable material;monitoring pressure of the material within the nozzle or proximal to thenozzle; flowing the material through an extrusion port of a nozzlecomprising a tapered inner surface; engaging a tapered end of a sealingneedle with the tapered inner surface of the nozzle, thereby sealing theextrusion port and stopping flow of the melted material; and withdrawingthe tapered end of the sealing needle, thereby resuming flow of thematerial through the extrusion port. In some embodiments, the methodcomprises withdrawing the tapered end of the sealing needle to aselected opening distance (e.g., a maximum open position). In someembodiments, the pharmaceutically acceptable material comprises a drug.In some embodiments, the method is performed using a device as describedherein. In some embodiments, the device includes a plurality of materialsupply systems, wherein each material supply system is configured with acontrol switch. In some embodiments, the control switch configured toeach material supply system is the same. In some embodiments, thecontrol switch configured to each material supply system is different(e.g., by using different actuators or sealing needles of differentdiameters). The method can include dispensing a first material from afirst material supply system and dispensing a second material from asecond material supply system, wherein the sealing needle of the firstmaterial supply system is in the closed position when the secondmaterial is dispensed from the second material supply system, and thesealing needle of the second supply system is in the closed positionwhen the first material is dispensed from the first material supplysystem. In some embodiments, the method further includes monitoringpressure of the first material within the first nozzle or proximal tothe first nozzle; and/or monitoring pressure of the second material withthe second nozzle or proximal to the second nozzle. In some embodiments,the method comprises withdrawing the tapered end of the second sealingneedle configured to the second material supply system to a selectedopening distance (e.g., a maximum open position), thereby adjusting theamount and/or speed of the flow of the second material through thesecond extrusion port.

In some embodiments, a method of manufacturing a pharmaceutical dosageform by additive manufacturing includes melting and pressurizing a firstpharmaceutically acceptable material; flowing the first pharmaceuticallyacceptable material through a first extrusion port of a first nozzlecomprising a tapered inner surface; engaging a tapered end of a firstsealing needle with the tapered inner surface of the first nozzle,thereby sealing the first extrusion port and stopping flow of the meltedfirst material; melting and pressurizing a second pharmaceuticallyacceptable material; and withdrawing a tapered end of a second sealingneedle from a tapered inner surface of a second nozzle, therebyinitiating flow of the second pharmaceutically acceptable materialthrough a second extrusion port. In some embodiments, the methodcomprises withdrawing the tapered end of the second sealing needle to aselected opening distance (e.g., a maximum open position), therebyadjusting the amount and/or speed of the flow of the secondpharmaceutically acceptable material through the second extrusion port.In some embodiments, the first pharmaceutically acceptable material orthe second pharmaceutically acceptable material is an erodible material.In some embodiments, the first pharmaceutically acceptable material orthe second pharmaceutically acceptable material comprises a drug. Insome embodiments, the method further comprises receiving instructionsfor manufacturing the pharmaceutical dosage form, for example from acomputer system. In some embodiments, the method further includesmonitoring pressure of the first material within the first nozzle orproximal to the first nozzle; and/or monitoring pressure of the secondmaterial with the second nozzle or proximal to the second nozzle.

In some embodiments, the pharmaceutical dosage form manufacturedaccording to the methods or using the device or systems described hereinincludes a multi-layered structure comprising a plurality of layers of afirst erodible material admixed with a drug, wherein the erosion of thefirst erodible material admixed with the drug correlates with releaserate of the drug from the pharmaceutical dosage form. Pharmaceuticaldosage forms, such as oral drug dosage forms, may provide any desireddrug release profile based on controlling various parameters, e.g.,thickness of a layer of a first erodible material admixed with a drug,surface area of the layer of the first erodible material, and drug massfraction of the layer of the first erodible material. Pharmaceuticaldosage forms with a desired drug release profile of a drug, or multipledrugs, may be readily designed and printed using the devices or systemsfor additive manufacturing as described herein.

The pharmaceutical dosage form manufactured according to the methods orusing the devices or systems as described herein can be designed toprovide a desired drug release profile. In some embodiments, thepharmaceutical dosage form is custom designed to provide a desired drugrelease profile, for example for use in personalized medicine. In someembodiments, the pharmaceutical dosage form comprises one or more layerscomprising a first erodible material admixed with a drug, wherein thefirst erodible material is embedded in a second material not admixedwith the drug. The pharmaceutical dosage form with the desired drugrelease profile can be designed, for example, by (a) selecting the firsterodible material and the second material for forming the pharmaceuticaldosage form; (b) obtaining an erosion rate of first erodible material;and (c) determining the thickness, surface area, and/or drug massfraction in each layer based on the release rate of the drug and thedesired drug release profile. In some embodiments, the pharmaceuticaldosage form further comprises one or more additional layers of a thirderodible material admixed with a second drug.

In some embodiments, the pharmaceutical dosage form comprises two ormore drugs, such as about any of 5 or more, 10 or more, 20 or more, 30or more, or 50 or more, wherein each drug has a desired drug releaseprofile. In some embodiments, the oral drug dosage form comprises two ormore drugs, wherein at least two drugs have a different desired drugrelease profile.

The desired release profile of the drug can be adjusted depending on thematerials and design used in manufacturing the pharmaceutical dosageform. In some embodiment, the pharmaceutical dosage form is manufacturedwith two or more different materials, which may be deposited using adevice described herein in one or more layers, which may be the same ordifferent. In some embodiments, the pharmaceutical dosage form includesa first layer with a first material with the drug admixed in the drug,and a second layer with a second material that does not include thedrug. In some embodiments, the pharmaceutical dosage form includes amulti-layered structure comprising one or more layers of a firsterodible material admixed with the drug, wherein the first erodiblematerial is embedded in a second material not admixed with the drug. Theerosion of the first erodible material admixed with the drug cancorrelate with release rate of the drug from the drug dosage form.

In some embodiments, the desired drug release profile comprises thefraction or percentage of total (i.e., cumulative) drug to be releasedfrom the oral drug dosage form by time points following administrationor subsequent commencement of drug release from the oral drug dosageform (e.g., for enteric-coated oral drug dosage forms). In someembodiments, the desired drug release profile is pre-determined.

In some embodiments, the drug will start to be released from an oraldrug dosage form once a layer of a first erodible material comprisingthe drug is exposed to a solution, such as oral fluid orgastrointestinal (GI) fluid. In some embodiments, the desired drugrelease profile of an oral drug dosage form is for the period of timefrom oral administration to complete release of a drug contained in theoral drug dosage form. In some embodiments, the desired drug releaseprofile comprises an initial delay period prior to a desired drugrelease period, wherein the initial delay period is a patient-specificperiod of time or an estimated period of time, e.g., due to use of anenteric-coated oral dosage form.

In some embodiments, the desired drug release profile of an oral drugdosage form comprises a zero-order release profile, a first-orderrelease profile, a delayed release profile, a pulsed release profile, aniterative pulsed release profile, an immediate release profile, asustained release profile, or a combination thereof.

In some embodiments, the total time of a desired drug release profile ofan oral drug dosage form is about 1 hour to about 72 hours, such as anyof about 1 hour to about 6 hours, about 1 hour to about 12 hours, about1 hour to about 18 hours, about 1 hour to about 24 hours, about 1 hourto about 30 hours, about 1 hour to about 36 hours, about 1 hour to about42 hours, about 1 hour to about 48 hours, about 1 hour to about 54hours, about 1 hour to about 60 hours, or about 1 hour to about 66hours. In some embodiments, the total time of a desired drug releaseprofile of an oral drug dosage form is about any of 1 hour, 2 hours, 3hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32hours, 34 hours, 36 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62hours, 64 hours, 66 hours, 68 hours, 70 hours, or 72 hours. In someembodiments, the total time of a desired drug release profile of an oraldrug dosage form is greater than or about 6 hours, greater than or about12 hours, greater than or about 18 hours, greater than or about 24hours, greater than or about 30 hours, greater than or about 36 hours,greater than or about 42 hours, greater than or about 48 hours, greaterthan or about 54 hours, greater than or about 60 hours, greater than orabout 66 hours, or greater than or about 72 hours. In some embodiments,the total time of a desired drug release profile of an oral drug dosageform is less than or about 6 hours, less than or about 12 hours, lessthan or about 18 hours, less than or about 24 hours, less than or about30 hours, less than or about 36 hours, less than or about 42 hours, lessthan or about 48 hours, less than or about 54 hours, less than or about60 hours, less than or about 66 hours, or less than or about 72 hours.

In some embodiments, one or more of the erodible materials is suitablefor admixture with a drug. In some embodiments, the erodible materialadmixed with the drug is chemically unreactive with a drug. In someembodiments, the erodible material is selected based on suitability foradmixture with a drug. In some embodiments, the erodible material isselected based on being chemically unreactive with a drug.

In some embodiments, the material admixed with a drug is a material thatsubstantially erodes (e.g., substantially complete erosion orsubstantially complete dissolution) during the time an oral drug dosageform is in an individual. In some embodiments, substantially all of theerodible material admixed with a drug in an oral drug dosage form erodesduring the time the oral drug dosage form is in an individual. In someembodiments, substantially all of a first erodible material admixed witha drug in an oral drug dosage form erodes during a desired time framethat the oral drug dosage form is in an individual. In some embodiments,substantially all of a first erodible material admixed with a drug in anoral drug dosage form erodes in less than about 72 hours, such as lessthan about any of 48 hours, 36 hours, 24 hours, 18 hours, 12 hours, 10hours, 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour.

In some embodiments, the erosion rate of a first erodible materialadmixed with the drug is between about 0.1 mm/hour to about 4 mm/hour.In some embodiments, the erosion rate of a first erodible materialadmixed with the drug is greater than about 0.1 mm/hour, such as greaterthan about any of 0.2 mm/hour, 0.4 mm/hour, 0.6 mm/hour, 0.8 mm/hour,1.0 mm/hour, 1.5 mm/hour, 2.0 mm/hour, 2.5 mm/hour, 3.0 mm/hour, 3.5mm/hour, or 4.0 mm/hour. In some embodiments, the erosion rate of afirst erodible material admixed with a drug is less than about 0.1mm/hour, such as less than about any of 0.2 mm/hour, 0.4 mm/hour, 0.6mm/hour, 0.8 mm/hour, 1.0 mm/hour, 1.5 mm/hour, 2.0 mm/hour, 2.5mm/hour, 3.0 mm/hour, 3.5 mm/hour, or 4.0 mm/hour.

Thickness of the deposited material (either the material admixed withthe drug or the material without the drug) can significantly alter therelease profile of a manufactured pharmaceutical dosage form. Thedevices and systems described herein allow for enhanced control over thethickness of the product, as the pressure of the device is carefullycontrolled and the control switch not only limits leakage of theextruded material but also modulates the amount and/or flow speed ofmaterial extrusion. Additionally, the device described herein limits“ramp up” of extrusion rate of the extruded material, which allows forbetter control of the material thickness.

In some embodiments, a method of manufacturing a pharmaceutical dosageform (such as a tablet) configured to provide a desired drug releaseprofile by additive manufacturing includes the steps of melting andpressurizing a first material comprising a drug; flowing the materialthrough a first extrusion port of a first nozzle comprising a taperedinner surface; engaging a tapered end of a first sealing needle with thetapered inner surface of the first nozzle, thereby sealing the firstextrusion port and stopping flow of the first melted material; meltingand pressurizing a second material; withdrawing a tapered end of asecond sealing needle from a tapered inner surface of a second nozzle,thereby flowing the second material through a second extrusion port. Insome embodiments, the method comprises monitoring pressure of the firstmaterial within the first nozzle or proximal to the first nozzle. Insome embodiments, the method comprises monitoring pressure of the secondmaterial within the second nozzle or proximal to the second nozzle. Insome embodiments, the method is performed using a device or system asdescribed herein.

EXEMPLARY EMBODIMENTS Embodiment 1

A device for depositing a material by additive manufacturing,comprising:

a material supply system configured to melt and pressurize the material,comprising a feed channel connected to a printing head comprising anozzle, the nozzle comprising a tapered inner surface and an extrusionport configured to dispense the material;

a pressure sensor configured to detect a pressure of the material withinthe nozzle or the feed channel proximal to the nozzle; and

a control switch comprising a sealing needle operable in an openposition and a closed position, the sealing needle extending through aportion of the feed channel and comprising a tapered end;

wherein the tapered end of the sealing needle engages the tapered innersurface of the nozzle to inhibit material flow through the nozzle whenthe sealing needle is in the closed position.

Embodiment 2

The device of embodiment 1, wherein the material is non-filamentous.

Embodiment 3

The device of embodiment 1 or 2, wherein any portion of the sealingneedle that contacts the material is free of protrusions.

Embodiment 4

The device of any one of embodiments 1-3, wherein the pressure sensor isconnected to a computer system that operates the material supply systemto pressurize the material to a desired pressure in response to thepressure reported by the pressure sensor.

Embodiment 5

The device of any one of embodiments 1-4, wherein the pressure of thematerial is within about 0.05 MPa of a desired pressure.

Embodiment 6

The device of any one of embodiments 1-5, wherein the material supplysystem comprises a piston and a barrel connected to the feed channel,and wherein the piston is operated to control the pressure of thematerial within the barrel.

Embodiment 7

The device of embodiment 6, wherein the piston is operated using astepper motor.

Embodiment 8

The device of any one of embodiments 1-7, wherein the tapered end of thesealing needle comprises a pointed tip.

Embodiment 9

The device of any one of embodiments 1-7, wherein the tapered end of thesealing needle is frustoconical.

Embodiment 10

The device of any one of embodiments 1-8, wherein the tapered innersurface of the nozzle has a first taper angle and the tapered end of thesealing needle has a second taper angle; and wherein the second taperangle is the same or smaller than the first taper angle.

Embodiment 11

The device of embodiment 10, wherein the second taper angle is about 60°or less.

Embodiment 12

The device of embodiment 10 or 11, wherein the second taper angle isabout 45° or less.

Embodiment 13

The device of any one of embodiments 10-12, wherein the ratio of thefirst taper angle to the second taper angle is about 1:1 to about 4:1.

Embodiment 14

The device of any one of embodiments 1-13, wherein the extrusion porthas a diameter of about 0.1 mm to about 1 mm.

Embodiment 15

The device of any one of embodiments 1-14, wherein the tapered end has alargest diameter of about 0.2 mm to about 3.0 mm.

Embodiment 16

The device of any one of embodiments 1-15, wherein the extrusion porthas a diameter and the tapered end has a largest diameter, and the ratioof the largest diameter of the tapered end to the diameter of theextrusion port is about 1:0.8 to about 1:0.1

Embodiment 17

The device of any one of embodiments 1-16, wherein the material has aviscosity of about 100 Pa·s or more when extruded from the device.

Embodiment 18

The device of any one of embodiments 1-17, wherein the material has aviscosity of about 400 Pa·s or more when extruded from the device.

Embodiment 19

The device of any one of embodiments 1-18, wherein the material melts atabout 50° C. to about 400° C.

Embodiment 20

The device of any one of embodiments 1-19, wherein the material isextruded from the nozzle at a temperature of about 50° C. to about 400°C.

Embodiment 21

The device of any one of embodiments 1-19, wherein the material isextruded from the nozzle at a temperature of about 90° C. to about 300°C.

Embodiment 22

The device of any one of embodiments 1-21, wherein the control switchcomprises an actuator that positions the sealing needle in the openposition or the closed position.

Embodiment 23

The device of embodiment 22, wherein the actuator is a pneumaticactuator.

Embodiment 24

The device of embodiment 22, wherein the actuator is a mechanicalactuator.

Embodiment 25

The device of embodiment 22, wherein the actuator is an electric motoractuator.

Embodiment 26

The device of embodiment 25, wherein the electric motor actuator is alinear stepper motor actuator.

Embodiment 27

The device of any one of embodiments 22-26, wherein the sealing needlepasses through a gasket fixed in position relative to the nozzle,wherein the gasket seals the feed channel.

Embodiment 28

The device of any one of embodiments 1-27, wherein the material supplysystem comprises one or more heaters configured to melt the material.

Embodiment 29

The device of embodiment 28, wherein the material supply systemcomprises one or more temperature sensors configured to detect thetemperature of the melted material.

Embodiment 30

The device of embodiment 29, wherein the one or more temperature sensorsare connected to a computer system that operates the one or more heatersin response to a temperature reported by the one or more temperaturesensors.

Embodiment 31

The device of any one of embodiments 1-30, wherein the tapered end ofthe sealing needle or the tapered inner surface of the nozzle comprisesa flexible pad or liner.

Embodiment 32

The device of any one of embodiments 1-31, further comprising a computersystem comprising one or more processors and a computer readable memory,wherein the computer system is configured to operate the device.

Embodiment 33

The device of embodiment 32, wherein the computer readable memorycomprises instructions for printing a product using the device.

Embodiment 34

The device of embodiment 32 or 33, wherein the computer readable memorycomprises instructions for controlling the pressure of the material inresponse to a pressure detected by the pressure sensor.

Embodiment 35

The device of any one of embodiments 32-34, wherein the computerreadable memory comprises instructions for controlling the temperatureof the material in response to a temperature detected by the temperaturesensor.

Embodiment 36

The device of any one of embodiments 33-35, wherein the computerreadable memory comprises instructions for positioning the sealingneedle based on the instructions for printing the product.

Embodiment 37

The device of embodiment 36, wherein the instructions for positioningthe sealing needle comprise instructions for selecting an openingdistance of the sealing needle based on a desired flow rate of thematerial from the extrusion port.

Embodiment 38

The device of any one of embodiments 1-37, wherein the pressure sensoris positioned proximal to the nozzle.

Embodiment 39

An additive manufacturing system comprising a plurality of devicesaccording to any one of embodiments 1-31, wherein each material supplysystem is configured with a control switch.

Embodiment 40

The system of embodiment 39, comprising a first device loaded with afirst material, and a second device loaded with a second material,wherein the first material and the second material are different.

Embodiment 41

The system of embodiment 39 or 40, wherein the control switch of eachdevice from the plurality of devices is different.

Embodiment 42

The system of embodiment 39 or 40, wherein the control switch of eachdevice from the plurality of devices is the same.

Embodiment 43

The system of any one of embodiments 39-42, further comprising acomputer system comprising one or more processors and a computerreadable memory, wherein the computer system is configured to operatethe system.

Embodiment 44

The system of embodiment 43, wherein the computer readable memorycomprises instructions for printing a product using the system.

Embodiment 45

The system of embodiment 43 or 44, wherein the computer readable memorycomprises instructions for controlling the pressure of the material ineach material supply system in response to a pressure detected by thepressure sensor in the corresponding material supply system.

Embodiment 46

The system of any one of embodiments 39-45, wherein the computerreadable memory comprises instructions for controlling the temperatureof the material in each material supply system in response to atemperature detected by the temperature sensor in the correspondingmaterial supply system.

Embodiment 47

The system of any one of embodiments 44-46, wherein the computerreadable memory comprises instructions for positioning the sealingneedle based on the instructions for printing the product.

Embodiment 48

The system of embodiment 47, wherein the instructions for positioningthe sealing needle comprise instructions for selecting an openingdistance of the sealing needle based on a desired flow rate of thematerial from the extrusion port.

Embodiment 49

The system of any one of embodiments 39-48, wherein at least two of thedevices from the plurality of devices comprise:

a material supply system configured to melt and pressurize the material,comprising a feed channel connected to a printing head comprising anozzle, the nozzle comprising a tapered inner surface and an extrusionport configured to dispense the material;

a pressure sensor configured to detect a pressure of the material withinthe nozzle or the feed channel proximal to the nozzle; and

a control switch comprising a sealing needle operable in an openposition and a closed position, the sealing needle extending through aportion of the feed channel and comprising a tapered end; and

wherein the tapered end of the sealing needle engages the tapered innersurface of the nozzle to inhibit material flow through the nozzle whenthe sealing needle is in the closed position.

Embodiment 50

The system of embodiment 49, wherein the tapered inner surface of thenozzle has a first taper angle and the tapered end of the sealing needlehas a second taper angle; and wherein the second taper angle is the sameor smaller than the first taper angle.

Embodiment 51

The system of any one of embodiments 39-50, wherein the pressure sensoris positioned proximal to the nozzle.

Embodiment 52

A method of manufacturing a product by additive manufacturing,comprising:

melting and pressurizing the material;

flowing the material through an extrusion port of a nozzle comprising atapered inner surface;

monitoring a pressure of the material within the nozzle or proximal tothe nozzle;

engaging a tapered end of a sealing needle with the tapered innersurface of the nozzle, thereby sealing the extrusion port and stoppingflow of the melted material; and

withdrawing the tapered end of the sealing needle, thereby resuming flowof the material through the extrusion port.

Embodiment 53

The method of embodiment 52, comprising receiving instructions formanufacturing the product.

Embodiment 54

A method of manufacturing a pharmaceutical dosage form by additivemanufacturing, comprising:

melting and pressurizing a pharmaceutically acceptable material;

monitoring a pressure of the material within the nozzle or proximal tothe nozzle;

flowing the material through an extrusion port of a nozzle comprising atapered inner surface;

engaging a tapered end of a sealing needle with the tapered innersurface of the nozzle, thereby sealing the extrusion port and stoppingflow of the melted material; and

withdrawing the tapered end of the sealing needle, thereby resuming flowof the material through the extrusion port.

Embodiment 55

The method of embodiment 54, wherein the pharmaceutically acceptablematerial comprises a drug.

Embodiment 56

The method of embodiment 55, wherein the pharmaceutical dosage form hasa desired drug release profile.

Embodiment 57

The method of any one of embodiments 54-56, comprising receivinginstructions for manufacturing the pharmaceutical dosage form.

Embodiment 58

The method of any one of embodiments 52-57, wherein the pressure of thematerial within the nozzle remains approximately constant.

Embodiment 59

The method of any one of embodiments 52-58, comprising controlling thepressure of the material using a feedback system based on the monitoredpressure.

Embodiment 60

The method of any one of embodiments 52-59, wherein the material isnon-filamentous.

Embodiment 61

The method of any one of embodiments 52-60, wherein any portion of thesealing needle that contacts the material is free of protrusions.

Embodiment 62

The method of any one of embodiments 52-61, wherein temperature of thematerial within the nozzle remains approximately constant.

Embodiment 63

The method of any one of embodiments 52-62, comprising monitoring thetemperature of the material.

Embodiment 64

The method of embodiment 63, comprising controlling the temperature ofthe material using a feedback system based on the monitored temperature.

Embodiment 65

The method of any one of embodiments 52-64, comprising withdrawing thetapered end of the sealing needle to a selected opening distance.

Embodiment 66

The method of any one of embodiments 52-65, wherein the tapered end ofthe sealing needle comprises a pointed tip.

Embodiment 67

The method of any one of embodiments 52-65, wherein the tapered end ofthe sealing needle is frustoconical.

Embodiment 68

The method of any one of embodiments 52-67, wherein the tapered innersurface of the nozzle has a first taper angle and the tapered end of thesealing needle has a second taper angle; and wherein the second taperangle is the same or smaller than the first taper angle.

Embodiment 69

The method of embodiment 68, wherein the second taper angle is about 60°or less.

Embodiment 70

The method of embodiment 68 or 69, wherein the second taper angle isabout 45° or less.

Embodiment 71

The method of any one of embodiments 68-70, wherein the ratio of thefirst taper angle to the second taper angle is about 1:1 to about 4:1.

Embodiment 72

The method of any one of embodiments 52-71, wherein the extrusion porthas a diameter of about 0.1 mm to about 1 mm.

Embodiment 73

The method of any one of embodiments 52-72, wherein the tapered end hasa largest diameter of about 0.2 to about 3.0 mm.

Embodiment 74

The method of any one of embodiments 52-73, wherein the extrusion porthas a diameter and the tapered end has a largest diameter, and the ratioof the largest diameter of the tapered end to the diameter of theextrusion port is about 1:0.8 to about 1:0.1.

Embodiment 75

The method of any one of embodiments 52-74, wherein the material has aviscosity of about 100 Pa·s or more.

Embodiment 76

A method of manufacturing a product by additive manufacturing,comprising:

melting and pressurizing a first material;

flowing the first material through a first extrusion port of a firstnozzle comprising a tapered inner surface;

engaging a tapered end of a first sealing needle with the tapered innersurface of the first nozzle, thereby sealing the first extrusion portand stopping flow of the melted first material;

melting and pressurizing a second material; and

withdrawing a tapered end of a second sealing needle from a taperedinner surface of a second nozzle, thereby initiating flow of the secondmaterial through a second extrusion port.

Embodiment 77

The method of embodiment 76, comprising receiving instructions formanufacturing the product.

Embodiment 78

A method of manufacturing a pharmaceutical dosage form by additivemanufacturing, comprising:

melting and pressurizing a first pharmaceutically acceptable material;

flowing the first pharmaceutically acceptable material through a firstextrusion port of a first nozzle comprising a tapered inner surface;

engaging a tapered end of a first sealing needle with the tapered innersurface of the first nozzle, thereby sealing the first extrusion portand stopping flow of the melted first material;

melting and pressurizing a second pharmaceutically acceptable material;and

withdrawing a tapered end of a second sealing needle from a taperedinner surface of a second nozzle, thereby initiating flow of the secondpharmaceutically acceptable material through a second extrusion port.

Embodiment 79

The method of embodiment 78, wherein the first pharmaceuticallyacceptable material or the second pharmaceutically acceptable materialis an erodible material.

Embodiment 80

The method of embodiment 78 or 79, wherein the first pharmaceuticallyacceptable material or the second pharmaceutically acceptable materialcomprises a drug.

Embodiment 81

The method of embodiment 80, wherein the pharmaceutical dosage form hasa desired drug release profile.

Embodiment 82

The method of any one of embodiments 78-81, comprising receivinginstructions for manufacturing the pharmaceutical dosage form.

Embodiment 83

The method of any one of embodiments 76-82, comprising monitoringpressure of the first material within the first nozzle or proximal tothe first nozzle; or monitoring pressure of the second material withinthe second nozzle or proximal to the second nozzle.

Embodiment 84

The method of any one of embodiments 76-83, wherein the pressure of thefirst material within the first nozzle, or the pressure of the secondmaterial within the second nozzle, remains approximately constant.

Embodiment 85

The method of any one of embodiments 76-84, comprising controlling thepressure of the first material or the second material using a feedbacksystem based on the monitored pressure.

Embodiment 86

The method of any one of embodiments 76-85, wherein the first materialor the second material is non-filamentous.

Embodiment 87

The method of any one of embodiments 76-86, wherein any portion of thefirst sealing needle that contacts the first material, or any portion ofthe second sealing needle that contacts the second material, is free ofprotrusions.

Embodiment 88

The method of any one of embodiments 76-87, wherein the temperature ofthe first material within the first nozzle, or the temperature of thesecond material within the second nozzle, remains approximatelyconstant.

Embodiment 89

The method of any one of embodiments 76-88, comprising monitoring thetemperature of the first material or the temperature of the secondmaterial.

Embodiment 90

The method of embodiment 89, comprising controlling the temperature ofthe first material using a feedback system based on the monitoredtemperature of the first material, or controlling the temperature of thesecond material using a feedback system based on the monitoredtemperature of the second material.

Embodiment 91

The method of any one of embodiments 76-90, comprising withdrawing thetapered end of the second sealing needle to a selected opening distance,

Embodiment 92

The method of any one of embodiments 76-91, wherein the tapered end ofthe first sealing needle, or the tapered end of the second sealingneedle, comprises a pointed tip.

Embodiment 93

The method of any one of embodiments 76-91, wherein the tapered end ofthe first sealing needle, or the tapered end of the second sealingneedle, is frustoconical.

Embodiment 94

The method of any one of embodiments 76-93, wherein:

the tapered inner surface of the first nozzle has a first taper angleand the tapered end of the first sealing needle has a second taperangle; and wherein the second taper angle is the same or smaller thanthe first taper angle; or the tapered inner surface of the second nozzlehas a third taper angle and the tapered end of the second sealing needlehas a fourth taper angle; and wherein the fourth taper angle is the sameor smaller than the third taper angle.

Embodiment 95

The method of embodiment 94, wherein the second taper angle or thefourth taper angle is about 60° or less.

Embodiment 96

The method of embodiment 94 or 95, wherein the second taper angle or thefourth taper angle is about 45° or less.

Embodiment 97

The method of any one of embodiments 94-96, wherein the ratio of thefirst taper angle to the second taper angle, or the ratio of the thirdtaper angle to the fourth taper angle, is about 1:1 to about 4:1.

Embodiment 98

The method of any one of embodiments 76-97, wherein the first extrusionport or the second extrusion port has a diameter of about 0.1 mm toabout 1 mm.

Embodiment 99

The method of any one of embodiments 76-98, wherein the tapered end ofthe first sealing needle or the tapered end of the second sealing needlehas a largest diameter of about 0.2 to about 3.0 mm.

Embodiment 100

The method of any one of embodiments 76-99, wherein the first materialor the second material has a viscosity of about 100 Pa·s or more.

Embodiment 101

The method of any one of embodiments 52-100, wherein the product or thepharmaceutical dosage form is manufactured in a batch mode.

Embodiment 102

The method of any one of embodiments 52-100, wherein the product or thepharmaceutical dosage form is manufactured in a continuous mode.

Embodiment 103

The product or the pharmaceutical dosage form made according to themethod of any one of embodiments 52-102.

EXAMPLES Example 1

Precision of a device described herein and as substantially illustratedin FIGS. 2A-B and FIG. 5A-5C was measured using a material containing80.75% Kollidon® VA64, 14.25% triethyl citrate (TEC), and 5% of a drugloaded into the barrel of the device. The material was heated to 110° C.in the barrel, to 110° C. in the feed channel, and to 135° C. in theprinting head. The printing head included a stainless steel nozzle witha 0.4 mm extrusion port. The material was pressurized to a desiredpressure of 0.5 MPa (±0.02 MPa) using a piston inserted into the barrel,controlled by a pressure controller in response to a pressure detectedby a pressure sensor. The sealing needle was positioned in the openposition for 2.50 seconds, 3.33 seconds, or 5 seconds, and the mass ofmaterial extruded through the extrusion port was measured. Results areshown in Table 1.

TABLE 1 Extrusion Time Number 2.5 seconds 3.33 seconds 5 seconds 1 7.5mg 11.5 mg 16.6 mg 2 7.4 mg 11.4 mg 16.2 mg 3 7.4 mg 10.6 mg 16.6 mg 47.5 mg 10.8 mg 16.4 mg 5 7.1 mg 10.9 mg 16.1 mg 6 7.6 mg 10.9 mg 16.1 mg7 7.2 mg 10.9 mg 16.0 mg 8 7.5 mg 10.9 mg 16.3 mg 9 7.0 mg 11.0 mg 16.3mg 10 7.4 mg 11.3 mg 16.0 mg 11 7.5 mg 10.8 mg 16.2 mg 12 7.4 mg 11.0 mg16.1 mg 13 7.5 mg 11.1 mg 16.1 mg 14 7.4 mg 10.9 mg 16.2 mg 15 7.5 mg11.1 mg 16.6 mg Standard Deviation 0.16 mg  0.23 mg 0.20 mg

Example 2

Precision of a device described herein and as substantially illustratedin FIGS. 2A-B and FIG. 5A-5C was measured using a material containing79.68% HPC, 19.92% triethyl citrate (TEC), and 0.4% of a drug loadedinto the barrel of the device. The material was heated to 90° C. in thebarrel, to 110° C. in the feed channel, and to 120° C. in the printinghead. The printing head included a stainless steel nozzle with a 0.3 mmextrusion port. The material was pressurized to a desired pressure of1.2 MPa (±0.05 MPa) using a piston inserted into the barrel, controlledby a pressure controller in response to a pressure detected by apressure sensor. The sealing needle was positioned in the open positionfor 1.25 seconds, 2.5 seconds, or 5 seconds, and the mass of materialextruded through the extrusion port was measured. Results are shown inTable 2.

TABLE 2 Extrusion Time Number 1.25 seconds 2.5 seconds 5 seconds 1 2.9mg 5.4 mg 10.2 mg  2 3.2 mg 5.0 mg 9.4 mg 3 2.8 mg 5.4 mg 9.5 mg 4 3.3mg 5.6 mg 10.3 mg  5 2.9 mg 5.3 mg 9.7 mg 6 3.0 mg 5.3 mg 9.8 mg 7 2.8mg 5.4 mg 9.8 mg 8 2.9 mg 5.5 mg 9.6 mg 9 3.0 mg 5.3 mg 9.9 mg 10 3.1 mg5.4 mg 9.6 mg 11 2.8 mg 5.2 mg 10.3 mg  12 3.1 mg 5.2 mg 9.5 mg 13 2.7mg 5.2 mg 9.0 mg 14 2.9 mg 5.3 mg 9.6 mg 15 3.0 mg 5.5 mg 10.3 mg Standard Deviation 0.16 mg  0.14 mg  0.37 mg 

Example 3

Precision of a device described herein and as substantially illustratedin FIGS. 2A-B and FIG. 5A-5C was measured using a material containing100% Eudragit® RSPO loaded into the barrel of the device. The materialwas heated to 140° C. in the barrel, to 140° C. in the feed channel, andto 165° C. in the printing head. The printing head included a stainlesssteel nozzle with a 0.3 mm extrusion port. The material was pressurizedto a desired pressure of 1.2 MPa (±0.05 MPa) using a piston insertedinto the barrel, controlled by a pressure controller in response to apressure detected by a pressure sensor. The sealing needle waspositioned in the open position for 1.67 seconds, 4 seconds, or 7seconds, and the mass of material extruded through the extrusion portwas measured. Results are shown in Table 3.

TABLE 3 Extrusion Time Number 1.67 seconds 4 seconds 7 seconds 1 4.9 mg9.1 mg 16.4 mg 2 4.7 mg 9.1 mg 16.6 mg 3 5.2 mg 9.3 mg 16.3 mg 4 4.8 mg8.9 mg 16.3 mg 5 4.9 mg 9.0 mg 16.5 mg 6 4.6 mg 9.5 mg 16.5 mg 7 4.9 mg9.2 mg 16.5 mg 8 4.9 mg 9.0 mg 16.9 mg 9 4.7 mg 9.2 mg 16.6 mg 10 4.8 mg9.2 mg 16.5 mg 11 5.1 mg 9.1 mg 16.2 mg 12 5.0 mg 9.2 mg 16.5 mg 13 4.8mg 9.0 mg 16.4 mg 14 4.7 mg 9.2 mg 16.2 mg 15 5.1 mg 9.2 mg 16.2 mgStandard Deviation 0.17 mg  0.14 mg  0.18 mg

Although examples of this disclosure have been fully described withreference to the accompanying drawings, it is to be noted that variouschanges and modifications will become apparent to those skilled in theart. Such changes and modifications are to be understood as beingincluded within the scope of examples of this disclosure as defined bythe appended claims.

What is claimed is:
 1. A device for manufacturing a pharmaceuticalproduct, comprising: a material supply system comprising a barrel, afeed channel, and a printing head, the barrel comprising a first heaterand configured to melt and pressurize a pharmaceutically acceptablematerial comprising a drug to convert the material into a meltedmaterial, the feed channel connecting the barrel to the printing head,and the printing head comprising a nozzle and a second heater, thenozzle comprising a tapered inner surface and an extrusion portconfigured to dispense the melted material, and the second heaterconfigured to heat melted material in the printing head to a temperatureabove the temperature of melted material in the feed channel; and acontrol switch comprising a sealing needle operable in an open positionand a closed position, the sealing needle extending straight through thefeed channel and comprising a tapered end; wherein the tapered innersurface of the nozzle has a first taper angle and the tapered end of thesealing needle has a second taper angle, and the second taper angle isthe same or smaller than the first taper angle, and wherein the taperedend of the sealing needle pierces the melted material in the printinghead to make the melted material to flow up, and engages the taperedinner surface of the nozzle to inhibit flow of the melted materialthrough the nozzle when the sealing needle switches to the closedposition.
 2. The device of claim 1, wherein the sealing needle isoperable in an open position between a maximum open position and aclosed position.
 3. The device of claim 1, wherein the tapered end ofthe sealing needle comprise a frustoconical tip.
 4. The device of claim1, wherein the tapered end of the sealing needle comprises a pointedtip.
 5. The device of claim 1, wherein the material has a viscosity ofabout 100 Pa·s or more when extruded from the device.
 6. The device ofclaim 1, wherein the control switch comprises an actuator that positionsthe sealing needle.
 7. The device of claim 6, wherein the actuator is apneumatic actuator, a mechanical actuator, or an electrical motoractuator.
 8. The device of claim 1, wherein the tapered end of thesealing needle or the tapered inner surface of the nozzle comprises aflexible pad or liner.
 9. The device of claim 1, further comprising acomputer system comprising one or more processors and a computerreadable memory, wherein the computer system is configured to operatethe device.
 10. The device of claim 9, wherein the computer readablememory comprises instructions for printing a product using the device.11. The device of claim 10, wherein the computer readable memorycomprises instructions for positioning the sealing needle based on theinstructions for printing the product.
 12. An additive manufacturingsystem comprising a plurality of devices for depositing a material byadditive manufacturing, wherein at least one of the devices is thedevice of claim
 1. 13. The system of claim 12, comprising a first deviceloaded with a first material, and a second device loaded with a secondmaterial, wherein the first material and the second material aredifferent.
 14. The system of claim 12, further comprising a computersystem comprising one or more processors and a computer readable memory,wherein the computer system is configured to operate the system.
 15. Thesystem of claim 14, wherein the computer readable memory comprisesinstructions for printing a product using the system.
 16. The system ofclaim 15, wherein the computer readable memory comprises instructionsfor positioning the sealing needle based on the instructions forprinting the product.
 17. The system of claim 12, wherein at least twoof the devices from the plurality of devices comprise: a material supplysystem configured to melt and pressurize the material to convert thematerial into a melted material, the material supply system comprising afeed channel connected to a printing head comprising a nozzle, thenozzle comprising a tapered inner surface and an extrusion portconfigured to dispense the material; and a control switch comprising asealing needle operable in an open position and a closed position, thesealing needle extending straight through the feed channel andcomprising a tapered end; and wherein the tapered end of the sealingneedle pierces the melted material in the printing head to make themelted material to flow up, and engages the tapered inner surface of thenozzle to inhibit flow of the melted material through the nozzle whenthe sealing needle switches to the closed position, and wherein thetapered inner surface of the nozzle has a first taper angle and thetapered end of the sealing needle has a second taper angle, and thesecond taper angle is the same or smaller than the first taper angle.18. The device of claim 1, wherein flow of the melted material from thefeed channel through the extrusion port is initiated when the sealingneedle switches from the closed position to the open position.
 19. Thedevice of claim 18, wherein an open distance of the sealing needle inthe open position modulates an amount or a speed of melted materialextruded from the nozzle.
 20. The device of claim 1, further comprisingthe material and the melted material.